Publication for Ldlr and Pcsk9

Species Symbol Function* Entrez Gene ID* Other ID Gene
coexpression		 CoexViewer
mmu Ldlr low density lipoprotein receptor 16835 [link]
mmu Pcsk9 proprotein convertase subtilisin/kexin type 9 100102

Pubmed ID Priority Text
23675525 0.99 PCSK9-dependent degradation of the LDLR.
0.98 Proprotein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of the LDLR in endosomes/lysosomes, resulting in increased circulating LDLc.
0.98 PCSK9 can also mediate the degradation of LDLR lacking its cytosolic tail, suggesting the presence of as yet undefined lysosomal-targeting factor(s).
0.98 LDLR is insensitive to PCSK9 in murine B16F1 melanoma cells, PCSK9 is able to induce degradation of the low density lipoprotein receptor-related protein 1 (LRP-1), suggesting distinct targeting mechanisms for these receptors.
0.98 PCSK9 enhances the degradation of cell surface LDLR in endosomes/lysosomes, resulting in increased circulating LDL cholesterol (LDLc).
0.98 Pcsk9 -/- mice exhibit higher levels of LDLR in liver and ~42% less circulating total cholesterol, with a ~80% drop in LDLc, emphasizing the therapeutic potential of a PCSK9 inhibitor/silencer.
0.98 PCSK9 binds at neutral pH to the EGF-A-like repeat of the LDLR via its catalytic domain.
0.98 LDLR either via an intracellular or extracellular pathway, the latter requiring secretion of PCSK9 and internalization of the cell surface [LDLR.PCSK9] complex into clathrin-coated pits.
0.98 PCSK9 on cell surface LDLR, and on its internalization in particular, have been demonstrated to also require the autosomal recessive hypercholesterolemia (ARH) adaptor protein.
0.98 PCSK9 to induce degradation of the LDLR.
0.98 LDLR in low metastatic B16F1 and highly metastatic B16F10 tumour cells (obtained by serial passage of B16F1 cells as lung nodules), both of which do not express PCSK9 mRNA endogenously (Figure 2A).
0.98 LDLR alone resulted in ~30% lower levels of endogenous LRP-1, suggesting the existence of a balance between LRP-1 and LDLR levels at the protein level, independent of PCSK9.
0.98 PCSK9 results in enhanced sorting of PCSK9 targets (e.g., LDLR, VLDLR and ApoER2) to the degradation pathway.
0.98 PCSK9 is required to effectively induce degradation of LRP-1, as was originally observed for LDLR and its closest family members VLDLR and ApoER2.
0.98 LDLR are not essential in mediating PCSK9-enhanced degradation (Figure 1), suggesting the presence of an additional factor(s) at the cell surface, which interacts with ARH through an NPXY motif.
0.98 LDLR, and its closest family members VLDLR and ApoER2, the catalytic domain of PCSK9 is necessary to bind the EGF-A domain of these receptors, but is not sufficient to induce their degradation.
0.97 LDLR in mediating its PCSK9-induced internalization and degradation.
0.97 PCSK9 is capable of inducing degradation of LRP-1, the latter is not an essential factor for LDLR regulation, but the LDLR effectively competes with LRP-1 for PCSK9 activity.
0.97 [LDLR.PCSK9] complex, the ability of PCSK9 to induce lysosomal degradation of the LDLR requires the presence of its CHRD.
0.97 PCSK9, Western blot analysis revealed no change in total or cell surface LDLR levels, emphasizing the importance of ARH in the mechanism of PCSK9-induced LDLR degradation.
0.97 PCSK9 to act on the LDLR in the absence of the receptor's CT, these findings would suggest the presence of an additional factor(s) at the cell surface, which potentially interacts with either the LDLR, PCSK9, or both to mediate the internalization and/or degradation of the [LDLR.PCSK9] complex.
0.97 PCSK9 to modulate LRP-1 protein levels and the possibility that PCSK9 may modulate differentially LRP-1 from the LDLR, and/or represent one of the sought co-factors in the PCSK9-induced LDLR degradation.
0.97 PCSK9 to act on DeltaCT suggests that LDLR's transmembrane domain (TMD) may participate in receptor sorting, or that LDLR has a co-receptor.
0.97 PCSK9 reduces cell surface LDLR levels independent of the receptor's CT and TMD.
0.97 PCSK9 alone resulted in a ~80% decrease in LRP-1, suggesting that LDLR is not needed for the PCSK9-mediated LRP-1 degradation.
0.97 PCSK9 is required for its binding to the LDLR, it is not sufficient to induce degradation of this receptor, requiring the CHRD for that purpose.
0.97 PCSK9-regulated degradation of the LDLR, we looked for membrane-bound proteins that contain an NPXY motif.
0.97 LDLR.PCSK9] complex to endosomes/lysosomes, it is a novel target of PCSK9.
0.97 PCSK9 to act on LRP-1 in B16F1/F10 melanoma cells (Figure 2), we discovered that PCSK9 is capable of enhancing LRP-1 degradation in both the B16F1 and the more metastatic B16F10 cells, but only the more active GOF PCSK9D374Y is capable of acting on the LDLR in B16F10, and not in B16F1 cells.
0.97 PCSK9 enhances the degradation of the LDLR family members VLDLR and ApoER2, and yet no effect was detected by Western blot of these receptors in livers from Pcsk9 -/- mice.
0.97 PCSK9 activity on LDLR, and it was also found that WT adrenals are refractory to PCSK9 activity, but LDLR levels in the adrenals of mice lacking Annexin A2 are sensitive to PCSK9.
0.96 PCSK9-regulated trafficking of the LDLR.
0.96 LDLR construct examined, exogenous PCSK9 resulted in a ~40-50% decrease in cell surface LDLR levels compared to cells treated with control conditioned media (Figure 1D).
0.96 PCSK9 enhances the degradation of LRP-1, and that the machinery to sort the [LDLR.PCSK9] and [LRP-1.PCSK9] complexes towards degradation compartments in B16F1 cells must be different.
0.96 PCSK9 and LRP-1 protein levels (Figure 4A), the presence of LDLR reduces the ability of PCSK9 to enhance the degradation of LRP-1 from ~80% to ~40%, indicating a competition between LDLR and LRP-1 for PCSK9.
0.96 LDLR was found to be the most upregulated (~2.5x, p<0.01) protein in Pcsk9 -/- livers, as previously reported.
0.96 LDLR.PCSK9] endocytosis was originally thought to be the LDLR itself.
0.95 proprotein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of the LDLR, and is well-established as a gene associated with familial hypercholesterolemia, along with LDLR, APOB and very recently APOE .
0.95 PCSK9 (Figure 2A), it was possible that exogenous PCSK9 could regulate the levels of LDLR or LRP-1 in B16 cells.
0.95 PCSK9 to induce the degradation of LRP-1 are similar to those needed to enhance the degradation of the LDLR and other family members.
0.95 LDLR (Figure S3) into the Q2954 and F2963 substitutions in LRP-1 result in a lower affinity for PCSK9, as predicted from our results (Figures 2 and 3), is not known, but may in part explain the lower efficacy of PCSK9 to enhance the degradation of LRP-1 compared to LDLR in most cell types, except for melanoma B16 cells.
0.94 LDLR was reduced by ~20% in cells treated with PCSK9 (Figure 1C).
0.94 PCSK9-LAMP1 induced degradation of both LRP-1 (~60% decrease) and LDLR (~90% decrease).
0.94 PCSK9 can enhance the degradation of LRP-1, the latter is not an essential factor for LDLR regulation, but LDLR can effectively compete with LRP-1 for PCSK9 activity.
0.92 PCSK9 resulted in a ~100% decrease in the levels of LDLR and a ~80% decrease in ~85 kDa LRP-1 (Figure 3A).
0.89 PCSK9D374Y mutant resulted in a ~60% reduction of LDLR levels (Figure 2B).
0.89 PCSK9 to degrade cellular LDLR (Figure 4B) and vice versa (Figure 4A).
0.88 PCSK9 can enhance the degradation of LRP-1, the latter is not a critical co-factor in the PCSK9-mediated degradation of the LDLR.
0.88 PCSK9 is favoured over LDLR, we conclude that in B16 melanoma cells the machinery to sort the [LDLR.PCSK9] and [LRP-1.PCSK9] complexes towards degradation compartments is different.
0.87 PCSK9 acts on the LDLR independent of the receptor's CT and TMD
0.87 PCSK9 acts on the LDLR independent of the receptor's CT and TMD.
0.86 LDLR co-receptor is recycled rather than degraded, it is possible that its levels would not be significantly altered by the absence of PCSK9.
0.80 PCSK9 to induce the degradation of LRP-1 and LDLR is similar (Figure 5), the critical PCSK9 residues seem to be somewhat different.
0.76 PCSK9 resulted in a ~20% increase in both LDLR and LRP-1 levels when normalized to beta-actin (Figure 3A).
0.72 PCSK9 binding residues in LDLR's EGF-A domain NECL319 and D331 are found in equivalent positions in LRP-1.
0.67 PCSK9 to act on the LDLR is not dependent on the receptor's CT or TMD.
0.66 PCSK9 contains D374 that forms a hydrogen bond with H327 of the LDLR.
28495363 0.99 PCSK9-mediated LDLR degradation.
0.98 PCSK9, but its role in PCSK9-mediated LDLR degradation remains controversial.
0.98 PCSK9 was previously shown to physically interact with APLP2 in a pH-dependent manner, but the importance of this interaction for PCSK9-mediated LDLR degradation remains controversial.
0.98 LDLR and PCSK9.
0.98 PCSK9-mediated LDLR degradation in vivo (Fig. 3, 4).
0.97 PCSK9 binds to the extracellular domain of the LDLR, and the PCSK9-LDLR complex is internalized through canonical clathrin-dependent endocytosis and then delivered to lysosomes for degradation.
0.97 PCSK9 binds the epidermal growth factor-like repeat (EGF)-A in the extracellular domain of the LDLR, and the PCSK9:LDLR complex is internalized by receptor-mediated endocytosis.
0.97 PCSK9 is not required for LDLR binding at the cell surface, although it is required for LDLR degradation.
0.97 PCSK9 for the LDLR by 50- to 150-fold.
0.97 PCSK9 interacts with other protein(s) that target the PCSK9:LDLR complex to the lysosome for degradation.
0.97 PCSK9-mediated LDLR degradation.
0.97 PCSK9 into the circulation in mice caused a rapid and substantial decrease in hepatic LDLR levels in both WT and App-/- mice.
0.97 PCSK9-mediated degradation of LDLR was preserved in the livers of App-/-, Aplp2-/-, APLP2-depleted App-/-, and liver-specific Lrp1-/- mice.
0.97 PCSK9 but is not required for PCSK9-mediated LDLR degradation in immortalized hepatocytes (HuH7 and HepG2) or primary hepatocytes.
0.97 PCSK9-mediated degradation of LDLR.
0.97 pcsk9-/- mice have a 2-fold increased LDLR protein level in their livers, while this change was not observed in App-/-, Aplp2-/-, or APLP2-depleted App-/- mice, which suggests that APP and APLP2 are not required for PCSK9-mediated LDLR degradation.
0.96 PCSK9 binds with cell surface LDLR, the PCSK9:LDLR complex is quickly internalized into the early endosome and is then targeted to the lysosome for degradation.
0.96 PCSK9-mediated LDLR degradation in mouse liver.
0.95 PCSK9-mediated LDLR degradation and are not regulated by PCSK9 in vivo.
0.95 PCSK9:LDLR complex is internalized by clathrin-dependent endocytosis, it is also delivered to the endosomal compartment.
0.95 PCSK9 preferentially reduces liver LDLR in mice.
0.94 PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo
0.94 PCSK9-mediated LDLR degradation, we examined the effects of disrupting these proteins in mice.
0.94 PCSK9 interacts with another protein(s) to target the PCSK9:LDLR complex to lysosomes.
0.94 PCSK9-mediated LDLR degradation, we tested whether PCSK9 promotes the degradation of LDLR in App-/- or Aplp2-/- mice.
0.94 PCSK9 and tested their potential roles in PCSK9-mediated LDLR degradation.
0.93 PCSK9 into App-/-, Aplp2-/, Aplp2-depleted App-/-, or liver-specific Lrp1-/- mice resulted in similar reductions in the levels of hepatic LDLR as seen in wild-type (WT) mice.
0.93 PCSK9 to LDLR; PCSK9 containing either of these two mutations exhibits an increased ability to degrade LDLR.
0.93 PCSK9-mediated LDLR degradation (Fig. 4B).
0.93 PCSK9-mediated LDLR degradation in liver-specific Lrp1 knockout mice
0.91 PCSK9-mediated LDLR degradation was also preserved in the livers of Aplp2-/- mice (Fig. 4A).
0.90 PCSK9-medicated LDLR degradation.
0.90 PCSK9-mediated LDLR degradation was preserved in liver-specific LRP1 knockout mice (Fig. 5A) and PCSK9 infusion did not affect the level of LRP1 in the liver (Fig. 5A).
0.90 PCSK9-mediated LDLR degradation and are not regulated by PCSK9 in vivo.
0.90 PCSK9 (32 mug/mouse) may have led to a significantly higher level than the endogenous one, which could mask the requirement of APP, APLP2 or LRP1 in PCSK9-mediated LDLR degradation.
0.89 PCSK9:LDLR complex is transported to lysosomes for degradation by a process that remains to be defined.
0.89 PCSK9-mediated LDLR degradation in the livers of Aplp2-/- mice and App-/-, APLP2-depleted mice
0.88 PCSK9-mediated LDLR Degradation in the Liver Does Not Require LRP1
0.86 PCSK9-mediated LDLR degradation.
0.86 PCSK9-mediated LDLR Degradation in the Liver Does Not Require APP and APLP2
0.85 PCSK9-mediated LDLR degradation or that circulating PCSK9 alters the levels of either of these two proteins.
0.84 PCSK9 does not bind to LDLR directly at the cell surface.
0.84 PCSK9-mediated LDLR degradation in App-/- mice
0.75 PCSK9-mediated LDLR degradation.
0.63 PCSK9 crosslinked to LDLR, APP, APLP2 and LRP1 in hepatocytes and mouse liver
26445568 0.99 PCSK9 promotes degradation of the LDLR extracellularly in an adaptor protein autosomal recessive hypercholesterolemia (ARH)-dependent manner in hepatocytes and lymphocytes.
0.98 PCSK9 binds to LDLR and promotes lysosomal degradation of the receptor, while IDOL down-regulates LDLR via the polyubiquitination and lysosomal degradation pathway.
0.98 PCSK9 expression in mice leads to increased levels of LDLR protein in the liver and accelerated LDL clearance.
0.98 PCSK9 in homeostatic control of plasma LDL-C levels is dependent upon PCSK9-promoted degradation of the LDLR, thereby preventing clearance of LDL-C by the cells.
0.98 PCSK9 strongly binds to the LDLR at the acidic endosomal environment, which blocks recycling of the LDLR to the cell surface.
0.98 PCSK9 causes degradation of the LDLR primarily through interaction with the receptor on the cell surface.
0.98 PCSK9 in cultured cells and mouse liver induces LDLR degradation intracellularly.
0.98 PCSK9 could act both intracellularly and extracellularly to promote LDLR degradation in cultured cells and mouse primary hepatocytes.
0.98 PCSK9 in mouse through infusion of purified PCSK9 or transgenic overexpression in the kidneys preferentially promote LDLR degradation in the liver but not in the adrenal glands.
0.98 PCSK9 directly interacts with annexin A2, which subsequently inhibits PCSK9-promoted LDLR degradation.
0.98 PCSK9 interacts with the EGF-A of the LDLR at the cell surface and binds the receptor with a much higher affinity at the acidic environment of the endosome (Fig. 2).
0.98 LDLR that are not required for PCSK9 binding at neutral pH are essential for efficient LDLR degradation induced by PCSK9.
0.98 LDLR may interact with the positively charged C-terminal domain of PCSK9 in the acidic endosomal environment, to enhance PCSK9 binding (Fig. 2, step 3).
0.97 LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 (SREBP-2) and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 (PCSK9) and inducible degrader of the LDLR (IDOL).
0.97 PCSK9-promoted LDLR degradation: (1) The catalytic domain and prodomain of PCSK9 bind to EGF-A and YWTD repeats of the LDLR, respectively.
0.97 PCSK9-promoted LDLR degradation in fibroblasts.
0.97 PCSK9 to LDLR interferes with the acid-dependent conformational change of the receptor but disrupting the pH-dependent conformational change in the LDLR is not sufficient to trigger LDLR degradation.
0.96 LDLR is also post-translationally regulated by proprotein convertase subtilisin/kexin-type 9 (PCSK9) and inducible degrader of the LDLR (IDOL).
0.96 PCSK9 in regulating the expression of the LDLR.
0.96 PCSK9-LDLR complex enters into cells via clathrin-dependent endocytosis and is delivered to the endosome.
0.96 PCSK9-LDLR complex shows that YWTD repeats of the LDLR interact with the prodomain of PCSK9.
0.96 PCSK9 to the LDLR reroutes the receptor to the lysosomes for degradation is not understood and is believed to be complex.
0.95 PCSK9-LDLR complex is transported to the lysosome for degradation.
0.93 PCSK9's action on the LDLR is cell-type specific.
0.93 PCSK9 or the LDLR contains a lysosomal targeting signal.
0.92 PCSK9-promoted LDLR degradation are not completely understood, which impedes the future design of PCSK9 specific small molecule inhibitors.
0.91 PCSK9 in the liver of mice causes a significant reduction in hepatic LDLR protein levels without any effect on its mRNA levels and produces severe hypercholesterolemia.
0.90 LDLR-H306Y, binds PCSK9 with a higher affinity and exhibits enhanced sensitivity to PCSK9.
0.90 PCSK9-promoted degradation of the LDLR requires binding of PCSK9 to the LDLR and internalization of the receptor but does not require the proteolytic activity of PCSK9.
0.90 PCSK9-EGF-AB complex show that the interaction face between the catalytic domain of PCSK9 and the EGF-A of the LDLR is relatively flat and big, making it impossible to design a specific inhibitor to block the interaction between PCSK9 and the EGF-A of the LDLR.
0.86 PCSK9-promoted LDLR degradation, such as identification of new interaction regions between PCSK9 and the LDLR and potential cofactors important for PCSK9-promoted LDLR degradation, are necessary.
0.84 PCSK9 is essential for PCSK9-promoted degradation of the LDLR but is not required for binding to the LDLR at the neutral pH values.
32169071 0.99 PCSK9 in the regulation of VLDLR seems to be similar to that observed in LDLR degradation, specifically, PCSK9 interacts with VLDLR by binding with the EGF-A domain to form an endocytosed complex that is degraded via lysosomal pathways (Fig. 1a).
0.98 PCSK9 expression in the kidney and its entry into the plasma resulted in considerably accelerated LDLR degradation in the liver, leading to an increase in the plasma LDL-C level.
0.97 LDLR-/-PCSK9-/- mice, the accumulation of Beclin-1 and p62 was markedly lower due to greater consumption of Beclin-1 and p62 and the conversion of LC3-I to LC3-II was increased over fourfold.
0.97 PCSK9 downregulates ABCA1 expression to inhibit ABCA1-mediated RCT dependent of LDLR.
0.96 PCSK9 in atherosclerosis-prone Apobec1-/-LDLR-/- mice caused the reduction in hepatic apoB secretion and the inhibition of the development of atherosclerosis.
0.95 PCSK9 obviously decreased the LDLR content of the duodenum and transintestinal cholesterol excretion in PCSK9 knockout (PCSK9-/-) mice.
0.95 PCSK9-overexpressing WT and LDLR-/- mice exhibited increased production of apoB. These results indicate that PCSK9 induces increased apoB secretion through an LDLR-independent pathway, thereby influencing the process of atherogenesis.
0.94 PCSK9 regulated the VLDLR levels in an LDLR-independent manner.
0.94 LDLR-/- mice than in WT/LDLR-/- mice, indicating that the overexpression of apoB was related to PCSK9 regardless of LDLR expression.
0.82 LDLR and PCSK9 knockout (LDLR-/-PCSK9-/-) mice, a similar 36-fold increase in the VLDLR level was observed.
0.79 PCSK9 failed to inhibit cholesterol efflux in LDLR-/- mice.
31317882 0.99 proprotein convertase subtilisin/kexin type 9 (PCSK9) can promote the degradation of LDLR in the cytoplasm and lysosomes by binding to the epidermal growth factor domain A (EGF-A) of the LDLR protein.
0.98 PCSK9 is a major endogenous promoter of LDLR degradation.
0.98 PCSK9 by downregulating the expression of HNF1alpha, and this leads to reduced degradation of LDLR in innate renal cells.
0.98 LDLR is a key regulator of lipid homeostasis in the kidney, and that PCSK9 has an important function in LDLR degradation.
0.98 PCSK9 by downregulating the expression of HNF1alpha in intrinsic renal cells, thereby reducing the degradation of LDLR and increasing the expression of SREBP2.
0.93 PCSK9 and its transcriptional activator (hepatocyte nuclear factor 1alpha, HNF1alpha) decreased, and the expression of the low-density lipoprotein receptor (LDLR) and its transcriptional activator (sterol regulatory element binding protein-2, SREBP-2) increased.
0.93 PCSK9 decreased, and the expression of LDLR increased.
31110520 0.99 PCSK9 binding leads to internalization and degradation of LDLR in the lysosomal compartment and thereby reduces recycling of LDLR to the cell surface.
0.96 PCSK9 circulates in the bloodstream and binds to the cell surface LDLR.
0.95 PCSK9 antibodies were found to inhibit the interaction between PCSK9 and LDLR.
0.86 PCSK9-LDLR interaction blockade by vaccine-induced PCSK9 antibodies
0.74 PCSK9 binding to LDLR by 53%, when compared with plasma sample of control group.
0.53 PCSK9 to LDLR was reduced by 53% in the presence of plasma obtained from L-IFPTA+-vaccinated mice, as compared to control mice (Figure 5 D).
22848640 0.98 PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR).
0.98 PCSK9, the 9th member of the proprotein convertase family, as a third protagonist in ADH has shed light on an unsuspected regulation of LDLR levels in liver and possibly in the brain.
0.98 PCSK9 binds the EGF-A domain of the LDLR via its catalytic domain and promotes its internalization and degradation in the endosome/lysosome pathway, independently of its enzymatic activity.
0.98 PCSK9 LDLR complex, since its deletion (aa 456-692) does not prevent PCSK9 binding to LDLR, but abrogates its ability to enhance its degradation.
0.98 Pcsk9-/- mouse livers exhibit ~3-fold more LDLR protein levels and a substantial accumulation of the receptor at the hepatocyte cell surface.
0.98 PCSK9 mRNA to a greater extent than LDLR.
0.98 PCSK9's function on the LDLR, through binding of the first R1 repeat domain of AnxA2 to the CHRD.
0.98 PCSK9 and lower LDLR protein levels in various tissues previously reported to be refractory to PCSK9's extracellular function on LDLR, such as the adrenals.
0.98 PCSK9 is highly expressed (Figure S2) and is the most active at inducing LDLR degradation.
0.98 PCSK9 that is secreted from hepatocytes, thereby decreasing its effect on LDLR.
0.97 PCSK9-Induced LDL Receptor Degradation
0.97 PCSK9 LDLR complex remain unclear.
0.97 PCSK9 levels in plasma could contribute to the observed ~40% increase in circulating LDLc levels seen in AnxA2-/- mice (Table 1, Figure S1) possibly through enhanced LDLR degradation.
0.97 LDLR but very low levels of PCSK9 mRNAs (Figure 2A, Figure S2).
0.97 PCSK9 is very low in adrenals, this decrease of LDLR may be the consequence of the ~2-fold higher levels of circulating PCSK9 in AnxA2-/- mice (Figure 1).
0.97 LDLR levels and plasma LDLc through the inhibition/capture of circulating PCSK9.
0.97 PCSK9 is available to degrade LDLR in a given organ.
0.97 PCSK9 and inhibit the function of this protein on LDLR, representing the first example of a natural inhibitor of PCSK9 activity.
0.97 PCSK9-induced LDLR degradation without affecting the PCSK9 LDLR interaction.
0.97 PCSK9 function on the LDLR internalization and degradation.
0.96 PCSK9 also binds and enhances the degradation of VLDLR and apoER2 that are closely related to LDLR.
0.96 LDLR level and activity thereby lowering LDLc, but on the other hand increase the expression of PCSK9 that has the ability to destroy the LDLR and oppose its LDL-lowering effect.
0.96 PCSK9 is much more active in enhancing LDLR degradation in AnxA2-/- mice.
0.96 PCSK9 induced LDLR degradation might either lack a specific regulator in these tissues, or that PCSK9 function may be inhibited therein.
0.96 LDLR levels were decreased by ~20% in the absence of AnxA2, but the reduction was much more marked in adrenals (~50%) and colon (~40%) (Figures 2,3), tissues known to be rich sources of AnxA2 (Figure S2), and resistant to PCSK9 effect.
0.96 PCSK9 such that its interaction with the LDLR, and/or its cellular internalization is compromised.
0.96 PCSK9 can reduce LDLR levels to the point that circulating LDLc are decreased, as observed in transgenic lines, and following injection of high doses of PCSK9.
0.95 PCSK9 LDLR interaction in vitro, and adenoviral overexpression of AnxA2 in mouse liver increases LDLR protein levels in vivo.
0.95 PCSK9's activity towards the LDLR led us to hypothesize that plasma cholesterol would be affected by the absence of AnxA2 in vivo.
0.95 LDLR levels in the ileum versus the colon, in absence of AnxA2, could arise from the differential expression of endogenous PCSK9 or the different accessibility of endogenous and circulating forms of PCSK9 to the LDLR.
0.95 PCSK9 and inhibit its interaction with LDLR, consistent with the activity seen for the full length AnxA2 protein.
0.95 PCSK9 in the bloodstream of mice spared the LDLR in a number of tissues, but was very active in selectively reducing the hepatic levels of this receptor.
0.95 PCSK9 LDLR complex?
0.94 PCSK9 LDLR complex to lysosomes for degradation has not been identified nor its sensitivity to AnxA2, since both proteins are predicted to bind the C-terminal CHRD of PCSK9.
0.94 PCSK9 LDLR interaction.
0.94 PCSK9 and/or its local bioavailability, and consequently its activity on LDLR.
0.93 PCSK9's ability to enhance the degradation of the LDLR, especially in adrenals and the digestive organs.
0.92 LDLR levels is not seen in Pcsk9-/- mice, attesting to the specificity of the AnxA2 effect, with the caveat that this could also relate to an already maximal response of LDLR expression in absence of PCSK9.
0.91 PCSK9 protein:protein interactions with the soluble LDLR ectodomain, we found that the long peptide form was the most potent inhibitor of PCSK9 binding to the LDLR.
0.91 LDLR protected from PCSK9-induced degradation?
0.91 PCSK9 LDLR interaction (Figure 4).
0.90 PCSK9 levels and/or function has been achieved by antisense mRNA, locked nucleic acids and inhibition of PCSK9 LDLR interaction and degradation using PCSK9 monoclonal antibodies (mAbs).
0.90 PCSK9 LDLR interaction and/or LDLR degradation.
0.88 Pcsk9 -/- mice, the immunostaining of hepatic LDLR appeared very strong as compared to WT livers, as previously reported.
0.87 Pcsk9 -/- mice did not modify the level of LDLR, as seen by Western blot and immunocytochemistry (Figure 5B,C), emphasizing the PCSK9-specificity of the Ad-A2 effect in WT mice.
0.86 LDLR for binding to PCSK9.
0.86 PCSK9 in hepatocytes or kidney also had little effect on LDLR levels in a number of extrahepatic tissues.
0.85 PCSK9 for the LDLR and results in very high circulating LDLc (~10 mmol/L) and early death due to CAD.
0.84 PCSK9 results in ~4-fold enhanced activity on LDLR.
0.84 LDLR-EGFA domain itself) that can significantly inhibit PCSK9 LDLR interaction.
0.81 LDLR in complex with PCSK9 did not show any interaction between the prosegment in mature PCSK9 and the CHRD at neutral pH. Therefore the role of the prosegment in regulating the extracellular PCSK9-AnxA2 interaction is not yet clear.
0.74 PCSK9 and its inhibition by quantifying LDLR activity at the cell surface will be needed to define if the V98L mutation modifies the function of PCSK9.
0.72 LDLR, the role of the latter and its lack of regulation by PCSK9 in presence of AnxA2 are yet to be better elucidated.
0.68 PCSK9 approaches used a small molecule inhibitor, possibly due to the relative flatness of the surface of interaction of the PCSK9 LDLR complex.
0.66 LDLR to PCSK9, we found that this 73 aa peptide can indeed compete with the LDLR for PCSK9 binding with an IC50 of 0.6 microM (Figure 4).
0.64 PCSK9 LDLR interaction in vitro
0.64 PCSK9 and increase LDLR protein levels in vivo, we used a recombinant adenovirus-mediated gene transfer technique to direct AnxA2 to the liver of mice.
0.58 low density lipoprotein receptor (LDLR; 67%), apolipoprotein B (apoB; 14%) or proprotein convertase subtilisin-kexin 9 (PCSK9; ~2%).
23690465 0.98 LDLR post-transcriptionally, PCSK9 has revolutionized our knowledge of cell-based control of cholesterol homeostasis .
0.98 LDLR-/- background, hepatic intracellular levels of hPCSK9 were lower than those in transgenic mice on WT background, suggesting that absence of LDLR reduces the amount of circulating PCSK9 captured by the cell, and that both newly synthesized and internalized hPCSK9 contribute to its cellular levels (Supplementary Figure 2C).
0.98 PCSK9 increases apoB secretion in hepatocytes and intestinal cells , and decreases VLDLR levels in adipocytes , provide a mechanistic basis for an LDLR-independent effect of PCSK9 on cholesterol levels.
0.98 mPCSK9 levels in WT but not in LDLR-/- mice, an effect likely due to the reduction in hepatic LDLR caused by hPCSK9, in turn impairing LDLR-mediated clearance of mPCSK9.
0.98 LDLR-/- background were two-times higher than those of transgenic mice on WT background (Figure 3), again showing that LDLR regulates serum levels of PCSK9 by acting as its primary clearance route.
0.98 LDLR-/- mice had lower levels of intra-hepatic hPCSK9, suggesting that internalization of PCSK9 by liver cells depends mainly on LDLR.
0.98 mPCSK9 and membrane LDLR.
0.98 PCSK9 is more active than its' monomer , thus suggesting that the LDL particle can directly influence PCSK9 activity in the serum and regulate LDLR levels in peripheral tissues.
0.97 Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels.
0.97 mPCSK9 levels in transgenic mice is probably due to hPCSK9-induced removal of hepatic LDLR, which in turn reduces mPCSK9 clearance.
0.97 LDLR-/- mice was similar to that of intravenously injected LDL (Supplementary Figure 4A), suggesting a dominant role for the LDLR in PCSK9 removal.
0.97 LDLR and PCSK9 in the adrenals compared to the liver of hPCSK9 transgenic mice (Supplementary Figure 6A).
0.97 PCSK9 increases serum cholesterol levels via both LDLR-dependent and LDLR-independent pathways, and that serum PCSK9 associates with LDL in a way that can affect peripheral or hepatic PCSK9 action.
0.97 PCSK9 effect on LDLR levels in adrenals, and provide results suggesting that higher levels of PCSK9 are needed to reduce LDLR levels in adrenals compared to liver, a phenomenon that is likely aggravated by the limited retention of circulating PCSK9 in the adrenal tissue.
0.97 PCSK9 is expressed in liver, small intestine, and kidneys, but its main target is hepatic LDLR .
0.97 LDLR levels in mice enabled us to show that LDLR is the primary route for serum PCSK9 clearance.
0.97 PCSK9 levels, hepatic LDLR levels, and serum LDL-c levels.
0.96 LDLR represents the main route of elimination of PCSK9, and a reciprocal regulation between these two proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
0.96 PCSK9 binds directly to LDLR, and the complex is internalized and targeted to the lysosomes for destruction .
0.96 PCSK9 is predominantly due to LDLR-mediated uptake.
0.96 PCSK9 is directly related to the levels of surface LDLR.
0.95 LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation.
0.95 LDLR is the primary route for serum PCSK9 clearance.
0.95 LDLR would deplete the PCSK9 pool and maintain proper LDL clearance, and a primary excess of PCSK9 would deplete the LDLR pool and cause serum LDL elevations.
0.94 LDLR+/- mice showed a 2.7-fold increase in serum mPCSK9 levels (to 429+-89 ng/ml), whereas acute over-expression of hLDLR reduced serum levels of mPCSK9 by 67% (to 53+-19 ng/ml), (Supplementary Figure 2B).
0.94 LDLR mutations that affect both LDL and PCSK9 clearance (e.g. receptor-negative mutations) aggravate hypercholesterolemia via the effect of accumulated PCSK9 on the normal LDLR allele product.
0.93 mPCSK9 were extremely elevated in LDLR-/- control compared to WT mice, but did not increase further in hPCSK9/LDLR-/- transgenic mice (Figure 3A).
0.93 mPCSK9 caused by absence of LDLR cannot be obviously modulated further by the expression of hPCSK9 (Figure 3).
0.93 LDLR-/- mice (slow), (Supplementary Figure 4), the absence of LDLR had a stronger effect on the half-life of hPCSK9 (9.7 fold increase over WT) than on that of LDL (5.2 fold increase over WT), suggesting that LDLR dependent clearance is actually more important to PCSK9 than to LDL.
0.92 PCSK9 levels by 4.3-fold in wild-type (WT) mice and not at all in LDLR-/- ice, where mPCSK9 levels were already 10-fold higher than in WT mice.
0.91 PCSK9 and LDLR, and its influence on lipid levels in the mouse.
0.90 LDLR-dependent uptake is the only known pathway for serum PCSK9 clearance, recent evidence suggests that the converse is not true, and reduced LDLR function does not affect clearance of serum PCSK9 , either due to LDLR-independent clearance routes or because a receptor that is dysfunctional in binding LDL may normally bind PCSK9.
0.90 PCSK9 , or at blocking circulating PCSK9 via neutralizing antibodies , as the only known effect of PCSK9 is the binding and degradation of LDLR .
0.89 mPCSK9 levels between WT and LDLR-/- mice.
0.89 PCSK9 and those of membrane LDLR.
0.89 PCSK9 injected in WT mice accumulates in the liver and kidney but not in the adrenals, and found a weaker association between PCSK9 and LDLR in the adrenals compared to liver.
0.88 LDLR is the dominant clearance route for serum PCSK9.
0.86 mPCSK9 levels are 9.5-fold higher in LDLR-/- mice compared to WT, whereas hPCSK9 levels are only 2-fold higher in hPCSK9/LDLR-/- mice compared to hPCSK9 WT.
0.85 PCSK9 can influence adrenal cell LDLR levels at all, we studied the effects of overexpression of hPCSK9, or its GOF mutation D374Y, in Y-1 cells.
0.82 PCSK9 and Cell Surface Low-Density Lipoprotein Receptor: Evidence for a Reciprocal Regulation
0.73 LDLR-/- mouse provides a unique system in which to study metabolism of both LDL and PCSK9 in the complete absence of LDLR.
0.72 PCSK9 levels, distribution, and activity as a function of LDLR expression, we developed a transgenic line of mice that express human PCSK9 (hPCSK9) in addition to their normal expression of murine PCSK9 (mPCSK9).
0.69 LDLR resulted in a 9.5-fold increase in mPCSK9 levels (1514+-245 ng/ml) compared to WT controls (160+-30 ng/ml).
0.64 PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9.
0.63 PCSK9 with its inherent drawbacks due to protein oxidation, or from the supra-physiologic levels of PCSK9 used in previous studies, causing an artificial exaggeration of the LDLR-independent clearance pathway.
0.61 PCSK9 overexpression on serum cholesterol levels in the absence of LDLR .
0.56 LDLR reduction there was no effect of hPCSK9 on other hepatic lipoprotein receptors, such as LRP1 (data not shown), and thus next we investigated the influence of PCSK9 on lipoprotein production.
0.54 LDLR+/- mice had 2.7-fold elevation in mPCSK9 levels and no elevation in cholesterol levels.
0.52 PCSK9 and LDLR expression in WT and hPCSK9 transgenic mice
24603306 0.98 Ldlr is controlled by the sterol-responsive element binding protein 2 (Srebp2), while its turnover depends on proprotein convertase subtilisin/kexin type 9 (Pcsk9), a serine protease.
0.98 Pcsk9 targets hepatic Ldlr for lysosomal degradation and thus prevents recycling of internalized Ldlr to the cell surface.
0.98 Ldlr and Pcsk9 mRNA expression, both were markedly increased at the protein level (Figure 3A and B).
0.98 Ldlr protein in liver cells is regulated via secreted Pcsk9, a serine protease that predominantly originates from the liver.
0.98 Ldlr, Pcsk9 targets this receptor for lysosomal degradation rather than for recycling to the cell surface.
0.98 Ldlr protein expression through a reduction in Pcsk9-mediated Ldlr degradation leading to decreased plaque formation.
0.97 Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation.
0.97 Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice.
0.97 Pcsk9 activity, we found an alternative route to decrease Pcsk9-mediated Ldlr degradation: pharmacological Sirt1 activation reduced hepatic Pcsk9 secretion, increased Ldlr expression, and decreased plasma LDL-cholesterol and atherosclerosis in mice.
0.97 Ldlr and Pcsk9 protein expression upon SRT3025 administration in cell lysates (Figure 4A and B).
0.97 Pcsk9 secretion and increased Ldlr expression as novel downstream effects of Sirt1 activity and highlight the potential of pharmacological Sirt1 activation as a novel anti-atherosclerotic strategy.
0.97 Ldlr protein expression in AML12 cells, while reducing the concentration of Pcsk9 in the supernatant and lowering the amount of Pcsk9 bound to Ldlr, despite no change in Pcsk9 transcription.
0.96 Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake.
0.96 Ldlr, Pcsk9, Pparalpha, Ppargamma, Srebp1, and Srebp2 (Figure 3A).
0.96 Ldlr and Pcsk9 were not altered by SRT3025 (Figure 4C), indicating that post-translational effects cause the changes in protein expression.
0.96 Pcsk9 and Ldlr after 24 h incubation with 10 muM SRT3025 revealed that Pcsk9 binding to Ldlr was impaired after SRT3025 treatment compared with vehicle control (Figure 4E).
0.96 Pcsk9 prevents SRT3025-induced increase in Ldlr expression and activity in AML12 hepatocytes.
0.96 Pcsk9 [3 ng ml-1, based upon concentrations measured in the supernatants of untreated AML12 (Figure 4D)] and SRT3025 to AML12 hepatocytes attenuated the drug-dependent increase in Ldlr protein expression (Figure 5A).
0.96 Ldlr is not defective and that limited extracellular availability of Pcsk9 contributes to the increase in Ldlr protein expression.
0.95 Pcsk9 secretion and enhancing Ldlr expression
0.95 Ldlr expression in AML12 hepatocytes and decreases Pcsk9 in the supernatant.
0.95 Pcsk9-dependent degradation of Ldlr in AML12 hepatocytes
0.95 Pcsk9 release, impairs Pcsk9 binding to hepatic Ldlr, and thereby prevents hepatic Ldlr degradation.
0.95 Pcsk9 levels in mice lacking Ldlr.
0.95 Pcsk9 to AML12 cells treated with SRT3025 decreased Ldlr protein expression and reduced LDL uptake by the cells.
0.95 Ldlr internalization and degradation are not disrupted by SRT3025 treatment and can be re-induced upon exogenous addition of Pcsk9.
0.95 Ldlr, but also plasma Pcsk9 activity, thus limiting its effect on LDL-cholesterol.
0.94 Ldlr protein expression upon Sirt1 activation is related to limited extracellular availability of Pcsk9 and/or a defective degradation of internalized Ldlr.
0.94 Pcsk9 also attenuated the drug-induced increase in LDL uptake (Figure 5B), consistent with the observed attenuation of Ldlr protein expression (Figure 5A).
0.94 Pcsk9 that contributes to the increase in Ldlr protein expression, suggesting that plasma Pcsk9 levels are an important determinant of hepatic Ldlr protein surface expression in our model.
0.93 Ldlr protein expression while decreasing plasma Pcsk9 in Apoe-/- mice.
0.93 Ldlr expression and Pcsk9 accumulation in AML12 hepatocytes
0.93 Pcsk9-dependent alterations on atherosclerosis may be hampered by reciprocal changes in Ldlr.
0.92 LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects.
0.91 Ldlr was reported to be the main route of Pcsk9 clearance.
0.87 Pcsk9 levels in Ldlr-/- mice were about 20-fold higher (Figure 7G).
0.86 Pcsk9 levels in Ldlr-/- mice (Figure 7G).
0.77 Ldlr expression and Pcsk9 accumulation in Apoe-/- mice
0.52 Ldlr-/- mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis.
22954675 0.98 PCSK9 has emerged as a key regulator of serum LDL-C metabolism by promoting the degradation of hepatic LDL receptor (LDLR).
0.98 PCSK9 is rapidly and efficiently secreted from liver into plasma where it binds to the EGF-A extracellular domain of LDLR.
0.98 PCSK9-LDLR protein complex is endocytosed, and traveled to the lysosome compartment for degradation within hepatocytes.
0.98 PCSK9 and LDLR genes are both modulated by sterol regulatory element binding proteins (SREBPs) through SRE motifs embedded in their proximal promoters.
0.98 LDLR and PCSK9 in hamster liver tissue were differentially regulated by nutrient deprivation.
0.98 PCSK9 expression and reduced LDLR protein abundance in mouse liver.
0.97 proprotein convertase subtilisin/kexin type 9 (PCSK9) as a new player in LDL metabolism through its interaction with hepatic LDLR.
0.97 PCSK9 as a natural LDLR degrader and the subsequent observations that PCSK9 mutations can profoundly affect LDL-C levels and the risk of CHD have galvanized great interest in understanding the in vivo regulation of plasma PCSK9 and its correlation with LDL-C levels.
0.97 PCSK9 mRNA levels and a reduced abundance of LDLR protein in hamster liver.
0.97 PCSK9 with concurrent increases in liver LDLR protein abundance provide new in vivo evidence to support the established role of PCSK9 in the control of plasma LDL-C metabolism under physiological regulations.
0.96 PCSK9-LDLR interactions by neutralizing antibodies, PCSK9 small interference RNAs and antisense RNAs as well as small molecule inhibitors of PCSK9 gene expression have been applied to lower circulating LDL levels via the diminution of PCSK9-mediated LDLR degradation.
0.96 PCSK9 with concomitant increases in LDLR protein levels in liver.
0.96 PCSK9 was lower in fasted animals was suggestive of increased uptake of LDL-C via elevated expression of LDLR on the hepatocytes of fasted hamsters.
0.96 PCSK9 and a concomitant increase in hepatic LDLR abundance in fasted hamsters.
0.95 PCSK9, LDL-C, and hepatic LDLR expression in hamsters and further delineated the molecular pathways involved in fasting-induced repression of PCSK9 transcription.
0.95 PCSK9 and LDLR in response to treatments of rosuvastatin (RSV) and a natural cholesterol lowering alkaloid berberine.
0.95 LDLR protein abundance, which occurred concurrently with the decline in serum PCSK9 and LDL-C levels.
0.95 PCSK9 mRNA levels markedly declined after 24 h of fasting, the mRNA levels of LDLR showed an early induction by fasting and returned to baseline level at 24 h and maintained at the basal level up to 48 h of fasting.
0.94 LDLR protein amounts via reductions of serum PCSK9 levels.
0.94 LDLR and PCSK9 with insignificant inhibitory effect on former and a strong suppression of latter.
0.94 PCSK9 gene expression and increases liver LDLR protein abundance
0.93 PCSK9 and LDL-C level, and hepatic LDLR mRNA and protein expressions during the prolonged fasting in hamster species.
0.90 PCSK9 mRNA and serum PCSK9 protein levels with concomitant increases of hepatic LDLR protein amounts.
0.90 PCSK9 and LDLR mRNA expressions in hamster liver
0.90 PCSK9 mRNA, we detected a 2.3-fold (p<0.001) increase in LDLR mRNA levels after 8 h of fasting, which returned to the level of fed state by 24 h and stayed at the baseline.
0.85 PCSK9 and LDL-C levels and increased liver LDLR protein abundance
0.81 PCSK9, limited studies have been conducted to examine the effects of physiological and nonpharmaceutical interventions on plasma PCSK9 levels and the correlation with hepatic LDLR abundances.
0.81 PCSK9, LDL-C and hepatic LDLR expression during fasting in the hamster species.
0.77 PCSK9 levels, and correlated that further with hepatic mRNA and protein expressions of LDLR and PCSK9.
0.75 LDLR protein were affected during fasting by the drastic reduction of plasma PCSK9 in those healthy individuals.
0.62 PCSK9 and LDL-C levels with alterations of relevant hepatic gene expression, utilizing real-time qPCR method, we compared mRNA levels of LDLR and PCSK9 in fed liver samples with that of fasted groups (Fig. 3A).
26833058 0.98 LDLR and GCK expressions through PCSK9.
0.98 LDLR protein levels, and inhibited PCSK9 expression in the liver.
0.98 PCSK9 binds to LDLR and then, reroutes it from the endosome to the lysosome, where the LDLR is degraded rather than recycling back to the cell membrane, thereby leading to an impaired cholesterol uptake and elevated serum cholesterol levels.
0.98 PCSK9, a protein that binds to LDLR and induces its degradation, and found that PCSK9 level was increased under the insulin-resistant conditions, which could be reversed by polydatin treatment (Fig. 1d) as expected (P < 0.001).
0.98 PCSK9 can bind to and induce the degradation of LDLR through both intracellular and extracellular pathways.
0.97 PCSK9 was interfered by siRNA, the upregulated effects of LDLR and GCK induced by polydatin under insulin-resistant conditions disappeared (Fig. 2c, d).
0.97 PCSK9 wild-type plasmid caused a sharp decline in LDLR and GCK expressions in the insulin-resistant group; these decreases, however, were restored by polydatin to nearly control levels (Fig. 2e, f).
0.97 PCSK9 expression (Fig. 4c) and increased protein levels of LDLR and GCK in db/db mice (Fig. 4d, e).
0.97 PCSK9-LDLR complex is formed in the endoplasmic reticulum and then transfers directly from the Golgi network to the lysosome.
0.97 PCSK9 binds to LDLR on the cell surface, followed by internalization and degradation of LDLR in lysosomes.
0.97 LDLR levels by repressing PCSK9 expression together with inhibiting the combination of PCSK9 and LDLR.
0.97 LDLR and GCK by affecting PCSK9.
0.96 LDLR and GCK expression possibly through PCSK9.
0.96 PCSK9 levels, siRNA-1153 could increase the expression of LDLR under the PA treatment conditions compared with the control group (Fig. 2c).
0.96 PCSK9 level and upregulated the protein levels of LDLR and GCK.
0.96 LDLR (160 KD) content pulled down by PCSK9.
0.95 PCSK9 plays a vital role in the degradation of low-density lipoprotein receptor (LDLR).
0.95 LDLR and GCK but down-regulated PCSK9 level in PA-induced insulin-resistant HepG2 cells
0.95 LDLR and GCK levels were both upregulated while the PCSK9 mRNA and protein levels were suppressed in db/db mice after polydatin treatment, corresponding to the vitro study.
0.95 PCSK9 and change the conformation of PCSK9, thereby blocking the interaction between PCSK9 and LDLR and the degradation of LDLR.
0.94 LDLR and GCK levels through down-regulating PCSK9 arouses our interest.
0.94 PCSK9 and LDLR (Fig. 2a).
0.94 LDLR levels by decreasing PCSK9 contents and inhibit the PCSK9-LDLR complex formed directly in the liver rather than an extracellular route.
0.93 LDLR expression accompanied by the decrease in PCSK9 level (Fig. 5a) and immunofluorescence staining revealed the co-location of LDLR and PCSK9 in the liver to some extent (Fig. 5b), which was consistent with the western blot results.
0.93 PCSK9 arouses our interest and we make a reasonable speculation that polydatin might increase LDLR expression through decreasing PCSK9 levels.
0.92 LDLR and PCSK9 in the liver.
0.89 LDLR with PCSK9 on the cell surface to some extent, consistent with a previous study.
0.86 LDLR and PCSK9 expression in the liver.
0.80 PCSK9 and LDLR, as well as insulin resistance, we sought to determine whether polydatin works by affecting PCSK9.
0.67 LDLR and GCK were disappeared in the PA + PCSK9 knockdown group.
0.55 PCSK9, LDLR, and GCK using an insulin-resistant cell model induced by PA.
20498851 0.98 PCSK9 accelerates the degradation of hepatic low density lipoprotein receptor (LDLR) and low levels of hepatic PCSK9 activity are associated with reduced levels of circulating LDL-cholesterol.
0.98 PCSK9 is thought to accelerate the degradation of hepatic low density lipoprotein receptor (LDLR) in endosomes/lysosomes by direct binding of the catalytic subunit of PCSK9 to the EGF-A domain of the LDLR.
0.98 LDLR degradation by PCSK9 exists in various cell types and that it is distinct from the extracellular one.
0.98 PCSK9 with a concomitant increase in cell surface LDLR protein levels.
0.98 PCSK9 down-regulates the protein levels of the LDLR by enhancement of its intracellular metabolic pathway in subcellular acidic compartments, without affecting LDLR mRNA levels.
0.98 Pcsk9 knock-out mice exhibit decreased levels of circulating LDL-C, demonstrably due to a high concentration of cell-surface hepatic LDLR.
0.98 PCSK9 was associated with a ~3-fold increase in the levels of LDLR protein (upper panel, Figure 4A).
0.98 PCSK9 protein by LNA ASO is accompanied by an increase in LDLR protein expression.
0.98 PCSK9 is its ability to reduce the protein level of hepatic LDLR, by dragging the latter towards endosomes/lysosomes for degradation.
0.98 PCSK9 mRNA levels associated with the presence of the LNA ASO, resulting in the reduction of PCSK9 protein amounts, also leads to a 1.5-fold increase in the cell surface protein expression of the LDLR.
0.98 PCSK9 down-regulates the expression of LDLR and thus directly participates in the aetiology of the hypercholesterolemia phenotype.
0.97 PCSK9 regulates LDLR degradation is not fully resolved, it seems to involve both intracellular and extracellular pathways.
0.97 PCSK9 mRNA resulted in an increase in LDLR protein but not LDLR mRNA levels, as also seen in vitro (Figure 4).
0.96 PCSK9 and Enhances LDLR Expression In Vitro and In Vivo
0.96 PCSK9 with a concomitant increase in LDLR protein levels after transfection in these cells.
0.96 PCSK9 over-expression in cell lines and direct intravenous injection of the protein to mice were shown to reduce LDLR levels and increase plasma LDL-cholesterol (LDL-C).
0.96 PCSK9 on LDLR degradation.
0.96 PCSK9 mRNA, with no observable effects on the mRNA expression levels of LDLR and HMGCoAR.
0.96 PCSK9 mRNA levels resulted in an immediate and significant up-regulation by 2.5-3 fold of the hepatic LDLR protein, an effect that lasted for at least 8 days (P<0.05) and was no significantly increased at day 16 (Figure 8).
0.96 PCSK9 and this in turn has enhanced the intracellular and surface expression levels of LDLR protein in cell lines being studied.
0.95 PCSK9-mediated degradation of LDLR would be valuable tools to control plasma LDL-cholesterol levels.
0.94 Pcsk9 gene, lead to decreased plasma LDL-C, and in mice to increased hepatic LDLR protein.
0.93 PCSK9 enhances expression of LDLR protein
0.93 PCSK9, results in a concomitant increase of total intracellular protein levels of the LDLR, without affecting its mRNA levels.
0.90 PCSK9 mRNA expression was found to be significantly reduced by the LNA ASO compared to saline (P<0.01 for all dose levels) dose-dependently and as expected with no effect on LDLR mRNA (Figures 7A and 7B).
0.90 PCSK9 gene expression, and thus inhibit the intracellular as well as extracellular pathways of LDLR degradation.
0.88 PCSK9 mRNA expression followed by an up-regulation of hepatic LDLR protein.
0.82 PCSK9 mRNA in liver, reduced circulating total cholesterol and LDL-C by 53% and 38%, respectively, and a 2-fold increase in the level of hepatic LDLR.
0.79 PCSK9 mRNA lasting for more than two weeks (A), with concomitant increase in LDLR protein (B).
0.62 LDLR and Apobec-1 were not influenced by treatment with the LNA ASO at any of the dose levels (Figure 7B), in agreement with the results observed in Pcsk9 knockout mice.
30582457 0.98 PCSK9 binds LDL receptor (LDLR) on the cell surface and upon internalization, directs it to lysosomal degradation, which results in decreased rate of removal of LDL-C from the circulation .
0.98 PCSK9 enhances the degradation of LDLR both extra- and intracellularly and contributes to LDL-C homeostasis.
0.98 PCSK9 is mediated through LDLR-dependent uptake, suggesting reciprocal regulation between these proteins .
0.98 PCSK9 in an LDLR-independent manner.
0.97 LDLR and PCSK9 protein levels in vivo.
0.97 PCSK9 completely abrogated the ability of Gcgr silencing to increase plasma LDL-C as sh-Gcgr treatment had no effect on plasma LDL-C (3.6 +- 1.1 mg/dl vs. 3.9 +- 1.2 mg/dl) in Pcsk9-/- mice (Online Figure VII) which may suggest a role for intracellular PCSK9 in LDLR and LDL-C regulation.
0.97 LDLR and plasma LDL-C through regulating PCSK9 protein levels.
0.97 PCSK9, Epac2 silencing led to decreased LDLR protein without a change in its mRNA levels (Figure 5E-F).
0.97 PCSK9 levels in LDLR deficient primary hepatocytes (Fig. 7A).
0.97 PCSK9 independent of LDLR and by enhancing the lysosome-mediated degradation of PCSK9.
0.96 LDLR in Gcgr-silenced mice correlated with an increase in circulating PCSK9 levels (295 +- 42 ng/ml vs. 597 +- 62 ng/ml) (Figure 1F).
0.96 Ldlr, Pcsk9, Hmgcr or Srebf2 (Figure 6D-F).
0.96 PCSK9 as a key regulator of LDLR recycling and plasma LDL-C gained extensive attention and rapidly translated into clinical practice .
0.94 PCSK9 and LDLR through Epac2 and Rap1.
0.94 PCSK9 levels were increased (145 +- 16 ng/ml vs. 365 +- 19 ng/ml) and liver LDLR protein was decreased (Figure 6B and 6C).
0.94 PCSK9 and LDLR through Epac2.
0.93 PCSK9, increased hepatic LDLR and a concomitant decrease in plasma LDL-C which was attributed to Gcgr action since activation of Glp-1 receptors alone had no effect on these parameters .
0.93 PCSK9 is routed to lysosomes for degradation and this effect is independent of LDLR .
0.93 LDLR protein, and increases hepatic and circulating PCSK9 in DIO mice.
0.92 PCSK9, plasma total and LDL-C without affecting Pcsk9 or Ldlr mRNA levels.
0.91 PCSK9, decreases hepatic LDLR protein and increases plasma total- and LDL-cholesterol in DIO mice.
0.89 PCSK9, this treatment also increased LDLR protein but not Ldlr mRNA (Figure 4F and4G).
0.87 LDLR in glucagon signaling-mediated regulation of PCSK9, we silenced Gcgr in LDLR knockout (KO) hepatocytes.
0.86 PCSK9 and resulted in lower LDL receptor protein and increased plasma LDL-cholesterol.
0.86 Pcsk9-/- and Ldlr-/- mice.
0.84 PCSK9 independently of LDLR.
0.80 PCSK9 (247 +- 25 ng/ml vs. 352 +- 28 ng/ml) without a change in hepatic Pcsk9, Ldlr, Hnf1a, and Srebf2 mRNA levels (Online Figure IV).
0.79 Ldlr-/-or Pcsk9-/- mice.
25682035 0.98 PCSK9 is functionally active in promoting hepatic LDLR degradation.
0.98 PCSK9 interact with hepatic LDLR and that both forms are functionally active in promoting LDLR degradation.
0.97 PCSK9 in mice; however, in hamsters HFD feeding led to elevated circulating LDL-C concentrations and increased plasma PCSK9 levels, which were accompanied by a significant reduction of liver LDLR amount.
0.97 PCSK9-DeltaN224 is functional in mediating hepatic LDLR degradation
0.97 PCSK9 and hepatic LDLR expression.
0.97 PCSK9 in 2003, various genetic engineered mouse models have been extensively utilized to demonstrate the function of circulating PCSK9 in mediating the degradation of hepatic LDLR protein and the consequential impact on plasma cholesterol levels.
0.97 PCSK9 levels was accompanied with marked reductions of hepatic LDLR protein in both hamster cohorts in response to HFD feeding.
0.97 PCSK9 with furin or PC5A, we demonstrate that the 53 kDa truncated PCSK9 species is capable of down-regulating LDLR protein levels in cultured hepatic cells, which were evident by the similar levels of endocytosed hamster PCSK9-M and hamster PCSK9-DeltaN in Huh7 cell lysates and the similar extent of reduction of LDLR protein levels in Huh7 cells by the two forms of hamster PCSK9.
0.95 PCSK9 and the reduction of liver LDLR protein in HFD-fed hamsters suggest that hamster is a better animal model than mouse to study the modulation of PCSK9/LDLR pathway by atherogenic diets.
0.95 PCSK9 concentrations and hepatic LDLR levels in mice and hamsters.
0.95 PCSK9 is capable of inducing hepatic LDLR degradation.
0.95 PCSK9 and hepatic LDLR in mice overexpressing PCSK9.
0.95 PCSK9 is functionally active in causing the hamster hepatic LDLR degradation.
0.94 PCSK9 knockout mice, liver LDLR protein was elevated nearly 3-fold and the plasma cholesterol levels fell by half.
0.94 PCSK9 serum levels in mice without a significant impact on liver LDLR protein levels.
0.93 PCSK9 mRNA and protein levels were both reduced in mice and hamsters by HFD feeding, however, liver LDLR protein levels were markedly reduced by HFD in hamsters but not in mice.
0.92 PCSK9 knockdown and overexpression have been widely used to study PCSK9-mediated hepatic LDLR degradation.
0.91 PCSK9 function in inducing LDLR degradation, hamster is a better model than mouse to study the modulation of PCSK9/LDLR pathway by dyslipidemic and atherogenic diets.
0.89 PCSK9, we assessed its function in causing the degradation of hepatic LDLR.
0.89 PCSK9 studies of genetic manipulations, limited studies have been reported to examine the interactive relationship between endogenous PCSK9 and hepatic LDLR protein in normal mice under different nutritional conditions.
0.88 PCSK9 levels without impacting on hepatic LDLR protein abundance in mice
0.86 PCSK9 and liver LDL receptor (LDLR) protein levels.
0.82 PCSK9 levels and hepatic LDLR expression.
0.67 PCSK9, and the increasing concentration of hamster PCSK9-DeltaN in the culture medium led to a corresponding decrease in LDLR protein levels in Huh7 cells.
0.58 LDLR protein levels are not sensitive to changes in endogenous serum PCSK9 levels.
30443213 0.98 PCSK9, an enzyme produced mainly in the liver, plays a critical role in cholesterol homeostasis regulation by binding LDLR and inducing LDLR degradation.
0.98 PCSK9 capable of binding LDLR.
0.98 PCSK9 is subsequently secreted into circulation from hepatocytes and functions by binding to the epidermal growth factor-like repeat A (EGF-A) domain on LDLR, resulting in hepatocyte endocytosis and lysosomal degradation.
0.98 PCSK9, and protodioscin was shown to further promote LDLR expression through reducing the PCSK9 level in vitro.
0.98 PCSK9/LDLR signaling pathway (Figure 7).
0.96 LDLR) and inducing LDLR degradation, proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis regulation.
0.96 PCSK9 and a remarkable decrease in the protein expression of liver LDLR compared with the mice in the control group (P < 0.01).
0.96 PCSK9 mostly acts extracellularly to cause subsequent degradation of LDLRs in liver cells; moreover, the study suggested that if an intracellular pathway exists, it only plays a minor role in LDLR regulation.
0.96 PCSK9 to a greater extent than the expression of LDLR, there is an increase in serum LDL-C, causing resistance to the LDL-cholesterol-lowering effect of statins and resulting in statin intolerance.
0.96 PCSK9/LDLR signaling pathway in ApoE-/- mice, while confirming that atorvastatin (10 mg/kg) promoted the upregulation of PCSK9 as well as LDLR.
0.95 PCSK9 mRNA in liver tissue and the circulating PCSK9 level in ApoE-/- mice were both reversed after DXXK treatment, and upregulation of LDLR in the liver was also detected in the protein level in DXXK-treated mice.
0.94 Proprotein convertase subtilisin/kexin type 9 (PCSK9), belonging to the proprotein convertase family, plays a critical role in cholesterol homeostasis regulation by binding and degrading the low-density lipoprotein cholesterol receptor (LDLR), leading to a decrease in hepatic cholesterol uptake and an increase in circulating LDL-C. Loss-of- and gain-of-function PCSK9 variants have been detected in hypocholesterolemia and hypercholesterolemia patients, respectively.
0.94 PCSK9 mRNA was increased and the expression of LDLR mRNA was decreased in high-fat diet-fed ApoE-/- mice (P < 0.01).
0.94 PCSK9/LDLR signaling pathway.
0.92 PCSK9/LDLR signaling pathway in the antihyperlipidemic effects (more specifically, the LDL-C-lowering effect) of DXXK using high-fat diet-fed ApoE-/- mice.
0.92 PCSK9 and LDLR mRNA expression (P < 0.05).
0.91 PCSK9 level (P > 0.05) in ApoE-/- mice fed a high-fat diet, but significantly increased the protein expression of liver LDLR (P < 0.01).
0.91 PCSK9/LDLR expression in ApoE-/- mice revealed in our study.
0.91 LDLR by PCSK9 is extremely complex and has only begun to be understood.
0.89 PCSK9/LDLR signaling pathway in the lipid-lowering and antiatherosclerotic effect of DXXK in high-fat diet-fed ApoE-/- mice.
0.82 PCSK9/LDLR pathway.
0.70 PCSK9 and LDLR mRNA Expression
0.67 PCSK9 level and liver LDLR protein expression.
27279328 0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-established down-regulator of LDLR, which acts by binding the receptor and causes its lysosomal degradation in cells.
0.98 PCSK9 expression directly influences atherosclerotic plaque composition with no changes in serum cholesterol levels, concurring with other studies suggesting that extra-hepatic tissues could significantly contribute to PCSK9 production and could potentially regulate LDLR expression.
0.98 LDLR is expressed on lymphatic endothelial cells of collecting lymphatic vessel and its level is modulated by PCSK9.
0.97 LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction, and bring forth a pleiotropic role for PCSK9 in lymphatic function.
0.97 PCSK9 and thus increased LDLR protein expression has a beneficial effect on collecting LV function throughout age when compared to wild type (WT) mice for up to six months, while displaying high expression of LDLR on LEC.
0.97 Pcsk9-/- mice displayed increased LDLR protein expression level compared to WT and Ldlr-/-; hApoB100+/+ mice.
0.97 LDLR levels in Pcsk9-/- mice are believed to accelerate clearance of circulating plasma ApoE-containing lipoprotein particles such as VLDL and HDL, and hence we surmise that HDL particles are cleared faster from the lymph of Pcsk9-/- mice.
0.96 Pcsk9-/- mice exhibited improved collecting lymphatic vessel function throughout age when compared to WT mice for up to six months, while displaying enhanced expression of LDLR on lymphatic endothelial cells.
0.96 PCSK9 prevents ApoB100 degradation, either directly or through a neutralizing effect on LDLR activity.
0.96 LDLR levels could be, at least in part, attributable to the presence of circulating PCSK9 in lymph.
0.96 Pcsk9-/- mice abundant in LDLR display improved lymphatic transport and as 3 month-old pre-atherosclerotic Ldlr-/-; hApoB100+/+ mice lacking LDLR showed a lymphatic dysfunction that was exacerbated in parallel to lesion formation, these results reinforce the idea that the LDLR per se could play a direct role on lymphatic function.
0.96 LDLR, our results suggest that lymphatic function also greatly benefits from downregulation of PCSK9.
0.96 PCSK9 level observed in Ldlr-/-; hApoB100+/+ mice causes excessive LDLR degradation on LEC.
0.96 PCSK9 resulted in increased LDLR expression on LEC and in improved lymphatic function of 6-month-old Pcsk9-/- mice compared to WT controls.
0.96 LDLR signalling might affect LEC function remain to be understood, our data suggest that LDLR per se could have a functional role in the early stage of lymphatic dysfunction, thus corroborating a novel pleiotropic effect of PCSK9 in arterial disease.
0.95 Pcsk9-/- mice when compared to atherosclerosis-prone Ldlr-/-; hApoB100+/+ and even WT mice.
0.95 PCSK9 levels, lymph isolated from the thoracic duct of Ldlr-/-; hApoB100+/+ mice tended to contain more circulating PCSK9 than WT animals (Fig. 4a,b; lymph isolated from Pcsk9-/- mice served as control).
0.94 Pcsk9-/- mice when compared to that of Ldlr-/-; hApoB100+/+ mice, signifying a more proper collecting LV function.
0.91 Ldlr-/-; hApoB100+/+ mice (Fig. 5a) that are not yet bearing atherosclerotic lesions (Supplementary Fig. S4a,c,d or accumulation of macrophages in the artery wall (Supplementary Fig. S4b,e. To support this, we showed that, in contrast to Pcsk9-/- mice (Fig. 1a), Ldlr-/-; hApoB100+/+ mice displayed an EB dye flow that was either interrupted (red arrows) or extravasated (yellow arrows) from the collecting LVs.
0.88 LDLR is present on LEC (Fig. 3a) and that this protein expression is increased in the absence of PCSK9 (Fig. 3b,c), we sought to determine the levels of circulating PCSK9 in lymph.
0.88 LDLR, particularly through PCSK9 inflection, on lymphatic function.
0.52 LDLR modulation on collecting LECs through PCSK9.
29180444 0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDL receptor (LDLR) and thereby promotes its intracellular degradation.
0.98 PCSK9 in LDb mice results in decreased production of hepatic apoB100-containing lipoproteins with modified lipid composition in conjunction with decreased atherogenesis via LDLR-independent mechanisms.
0.97 PCSK9 contributes to the development of atherosclerosis in mice in an LDLR-dependent manner.
0.97 PCSK9 contributes to atherosclerosis development via an LDLR-dependent mechanism.
0.97 PCSK9 regulates apoB synthesis and secretion through an autophagic process and that this effect is independent of the LDLR.
0.97 PCSK9 in primary hepatocytes of C57BL/6J, Ldlr-/-, and LDb mice, resulting in increased apoB synthesis and secretion, as demonstrated by pulse-chase experiments.
0.97 PCSK9 in animals lacking the LDLR reduced the secretion of apoB by increasing the autophagy signaling pathway and autophagy flux in hepatocytes.
0.96 LDLR and apoE are required to mediate the PCSK9 effect on atherosclerosis in mice.
0.95 PCSK9 increases hepatic apoB-containing lipoproteins in an LDLR-independent fashion.
0.95 PCSK9 was associated with VLDL and LDL separated from plasma using FPLC in Ldlr-/- and LDb mice (Fig. 6A).
0.94 Pcsk9 gene from atherosclerosis-prone LDb mice substantially reduced atherosclerosis, a benefit that was LDLR independent.
0.94 PCSK9 increases intestinal microsomal TG transfer protein mRNA levels independently of the LDLR.
0.93 LDLR by PCSK9 and the contributions of PCSK9 to atherogenesis are complex and not completely understood.
0.93 Pcsk9-/-, Ldlr-/-, and LTp mice (P = 0.0019, 0.0048, 0.0011, and 0.0081, respectively) compared with the corresponding PBS-treated mice.
0.93 PCSK9 is associated with VLDL and LDL from Ldlr-/- and LDb mice.
0.90 PCSK9 decreased plasma lipids and plasma apoB100, irrespective of the presence of LDLR.
0.90 PCSK9 reduces atherogenesis via mechanisms independent of the LDLR.
0.89 PCSK9 also stimulates intestinal microsomal triglyceride (TG) transfer protein independently of the LDLR.
0.86 Ldlr-/- and LTp mice were similar and the effects of these two LDLs on responses to ECs were also similar, which may explain the observation by Denis et al. that PCSK9 does not play a role in atherogenesis in Ldlr-/- mice.
0.77 PCSK9 contributed to the induction of gene expression on ECs, whether the effect on gene expression was similar between LTp-LDL and Ldlr-/--LDL, and whether LDb-LDL was more atherogenic than that from LTp or Ldlr-/- mice.
0.75 mPCSK9 and LDL from Ldlr-/-, LTp, and LDb mice on proatherogenic and autophagy gene expression in MCECs.
0.69 PCSK9 on LDL and apoB, and perhaps atherogenesis, are not entirely determined by the interaction of PCSK9 with the LDLR.
27050512 0.98 Pcsk9, which encodes a protein that is mainly synthesized and secreted from liver and induces degradation of hepatic LDLR, expression of other SREBP target genes, including Ldlr, was unchanged in tumor-bearing mice (Figure 3C).
0.98 PCSK9 is responsible for reduced LDLR content in liver, which might be initiated by AMPK-mediated mTORC1 inhibition.
0.98 Pcsk9 expression and consequently LDLR degradation in mouse liver.
0.98 PCSK9-LDLR axis and SREBPs in tumor-bearing mice (Figure S6E), suggesting an indirect inflammatory regulation of hepatic LDL clearance.
0.98 PCSK9-mediated degradation of LDLR.
0.98 PCSK9 resulting in elevated plasma PCSK9 concentrations and reduced hepatic LDLR protein abundance.
0.98 LDLR protein regulation by PCSK9 renders the liver the most responsive organ, eliminating adverse effects on tumor LDLR-mediated VLDL remnant/LDL uptake and thus suppressing tumor growth.
0.98 PCSK9 was reported to be involved in the maintenance of hepatic LDLR abundance.
0.98 PCSK9 binding to LDLR occurs either at the cell surface or in the trans-Golgi, leading to lysosomal degradation of both proteins.
0.98 PCSK9-mediated degradation of LDLR protein is mainly augmented by activation of hepatic PCSK9 and HNF1alpha, resulting in hypercholesterolemia.
0.97 PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover.
0.97 PCSK9-LDLR signaling axis.
0.97 PCSK9 and LDLR in liver in distinct physiological and pathological settings.
0.97 PCSK9-mediated LDLR degradation in liver causes insufficient LDL turnover and results in the elevation of plasma LDL.
0.96 LDLR protein levels in TPBC tumor-bearing mice is independent of SREBP signaling but dependent on PCSK9.
0.96 Pcsk9 and other SREBP target genes was downregulated in both LLC and melanoma B16 groups (Figure S3E), although hepatic LDLR protein remained unchanged (Figure S3F).
0.96 LDLR protein abundance together with elevated concentrations of both PCSK9 and LDL in LLC and, to a lesser extent, in B16 tumor-bearing mice.
0.95 Pcsk9 expression in TPBCs might contribute to LDLR reduction in liver, which is not observed in LLC or B16 tumor-bearing mice.
0.92 PCSK9 concentration might be due to binding of PCSK9 to LDL, which prevents clearance of circulating PCSK9 and degradation of LDLR.
0.89 LDLR in Ces3/Tgh-/- Mice via Attenuation of PCSK9 Activation
0.86 LDLR Expression via PCSK9 Inhibition
29495280 0.98 PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation.
0.98 PCSK9 had no effect on either Ldlr-/- or Apoe-/- mice, thus suggesting that both LDLR and ApoE are required for the function of PCSK9.
0.98 PCSK9 was found to be essential to induce LDL receptor degradation.
0.97 PCSK9 decreases the number of LDLR, which are available to be recycled back to the cell surface to remove LDL from the plasma.
0.97 LDLR mRNA significantly increased after immunogen X-PCSK9-B1 treatment, compared to the PBS-treated group (Figure 6, p = 0.0363 and 0.0030, respectively).
0.97 LDLR mRNA levels, resulting from the inhibition of the interaction of PCSK9 with LDLR.
0.97 LDLR protein were significantly increased in both C57BL/6J and Apoe-/- mice (Figure 7, p = 0.0039, 0.0376, respectively) after X-PCSK9-B1 immunogen treatment.
0.96 PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels
0.96 LDL receptor mRNA, but increased LDL receptor protein levels, this study noted that mice treated with X-PCSK9-B1 increased both the levels of LDL receptor mRNA and protein.
0.94 LDL Receptor mRNA: X-PCSK9-B1 Treatment Increased Hepatic LDL Receptor mRNA Level in Both C57BL/6J and Apoe-/- Mice
0.94 LDL receptor were significantly increased at day 120 after X-PCSK9-B1 treatment in both C57BL/6J and Apoe-/- mice.
0.94 LDL receptor proteins were significantly increased after X-PCSK9-B1 treatment in both C57BL/6 and Apoe-/- mice and after X-PCSK9-A2 treatment in Apoe-/- mice.
0.93 PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment.
0.92 PCSK9 mutation leads to lower amounts of LDLR, hence higher levels of LDL cholesterol.
0.92 PCSK9 decreased cholesterol and triglyceride levels and increased LDL receptor mRNA and proteins.
0.90 PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes.
0.90 PCSK9-A2 treatment also significantly increased LDLR protein levels in Apoe-/- mice (p = 0.0198).
0.88 PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed.
0.87 PCSK9 (X-PCSK9) to be used as immunogens, thus developing an active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDLR, which will in turn result in lower plasma cholesterol levels.
0.80 PCSK9 on lipid and lipoprotein levels were LDLR dependent, but ApoE independent.
23135270 0.98 PCSK9 prevents LDL receptor recycling by directing the ligand receptor complex for lysosomal degradation, resulting in reduced LDL cholesterol (LDL-c) clearance and increased plasma LDL-c levels.
0.98 PCSK9 binds to the EGF(A) domain of LDL receptor in a calcium-dependent fashion.
0.98 PCSK9 is required for autocatalytic processing of the single-chain PCSK9 precursor in the endoplasmic reticulum but not for LDL receptor binding and LDL receptor degradation.
0.98 LDL receptor PCSK9 complex revealed that the EGF(B) domain of LDL receptor is located close to the 218 loop, suggesting that Ab-3D5 may interfere with LDL receptor binding.
0.97 LDL receptor and blood cholesterol levels appear to be regulated by both species of circulating PCSK9, the intact and the cleaved forms.
0.96 PCSK9 reduced surface LDL receptor levels in a concentration-dependent fashion with a half-maximal reduction at 3.7-11 mug/ml (Fig. 6).
0.95 PCSK9 degrades liver LDL receptor and increases serum cholesterol levels.
0.94 PCSK9 is able to regulate LDL receptor and serum cholesterol levels, although somewhat less efficiently than intact PCSK9.
0.94 LDL receptor binding affinity of cleaved PCSK9 is best understood in the context of localized structural effects on this interaction.
0.92 LDL receptor binding to PCSK9 (supplemental Fig. S3A).
0.90 Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Active and Modulates Low Density Lipoprotein Receptor and Serum Cholesterol Levels
0.88 LDL receptor degradation by furin-cleaved PCSK9 in cellular assays.
0.87 LDL receptor PCSK9 complex provides a basis for our attempt to rationalize the moderate effect of cleavage on LDL receptor binding.
0.83 LDL receptor with activities that were only slightly reduced compared with intact PCSK9.
0.82 PCSK9 is no longer able to degrade LDL receptor.
0.80 PCSK9 protein for functional studies in biochemical assays and for in vivo LDL receptor degradation.
0.79 PCSK9c_fu and PCSK9c_hep also reduced LDL receptor surface levels in a concentration-dependent fashion.
0.75 PCSK9 is biologically inactive but would retain LDL receptor binding, then the circulating cleaved PCSK9 could act as a competitive inhibitor of the intact form.
0.69 PCSK9c_fu and intact PCSK9 almost completely reduced liver LDL receptor levels at the 45-mug dose (Fig. 7A).
23883163 0.98 LDLR and APOE are important factors for PCSK9-mediated HDL regulation.
0.98 PCSK9 in LDL cholesterol and lipid homeostasis is degradation of the LDL receptor (LDLR), VLDL receptor (VLDLR) and LDLR-related protein 8 (LRP8).
0.97 PCSK9 combined with the absence of LDLR resulted in a 1.2-fold induction of HDL cholesterol levels (115.5 +- 4.5 mg/dl vs 90.3 +- 3.4 mg/dl, P < 0.001), indicating that PCSK9 does not completely rely on an LDLR-dependent mechanism to regulate HDL cholesterol concentration.
0.97 Pcsk9/Apoe double-KO males, suggesting that the PCSK9-mediated HDL cholesterol regulation is dependent on the presence of APOE and that the role of APOE entirely depends on its ability to mediate the binding of HDL to LDLR or VLDLR.
0.97 PCSK9 controls circulating cholesterol concentrations by regulating both LDL and HDL levels through LDLR.
0.96 PCSK9-mediated HDL regulation : either LDLR-dependent or LDLR-independent : completely relies on APOE.
0.96 LDLR and Pcsk9 KO mice exhibiting 2- to 3-fold higher levels of LDLR in the liver, we hypothesized that rapid clearance of APOE-containing HDL via LDLR might be the major cause of decreased HDL cholesterol concentration in Pcsk9 KO mice.
0.96 Pcsk9/Ldlr double-KO mice were 21% lower than in Ldlr KO mice, revealing an LDLR-independent effect of PCSK9.
0.94 LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential.
0.94 LDLR plays an important role in PCSK9-mediated regulation of HDL cholesterol concentration, PCSK9 does not entirely rely on LDLR and that PCSK9-mediated regulation of HDL cholesterol concentration relies entirely on the presence of APOE.
0.94 PCSK9 is mainly through LDLR-mediated APOE-containing HDL clearance and that other targets of PCSK9 might be involved in the process.
0.93 LDLR is an important component of the mechanism because LDLR is a receptor that binds APOE in lipoproteins and the LDLR level is increased in Pcsk9 KO mice.
0.92 LDLR plays an important role in PCSK9-mediated HDL cholesterol regulation, it is not a unique factor implicated in this process.
0.91 LDLR, VLDLR, and LRP8 by PCSK9 inhibition.
0.87 Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation.
0.86 Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls.
0.85 PCSK9 regulates HDL cholesterol concentration through LDLR and APOE
0.60 LDLR was the unique receptor for the PCSK9-mediated HDL regulation by measuring HDL cholesterol concentrations in Ldlr KO, Pcsk9/Ldlr double-KO and wild-type control mice (Figure 4).
0.54 Pcsk9/Ldlr double-KO and Pcsk9/Apoe double-KO mice.
32058941 0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that down-regulates hepatic low-density lipoprotein receptor (LDLR) by binding and shuttling LDLR to lysosomes for degradation.
0.98 PCSK9 binds to the extracellular epidermal growth factor-like repeat A (EGF-A) domain of LDLR, causing its internalization.
0.97 PCSK9 at both mRNA and protein levels and increased the cellular LDLR protein level and its mediated cellular LDL-C uptake.
0.97 LDLR, have also been proven to stimulate PCSK9 gene expression, thus diminish the beneficial effects of statin treatment.
0.97 PCSK9 protein level and led to an increase in the following LDLR expression in the liver as supposed (Suppl Fig. 4).
0.96 PCSK9 expression/secretion and increased LDLR expression.
0.96 PCSK9 and LDLR protein level in the liver, implying more complex regulation mechanism of these 2 compounds (Suppl Fig. 4).
0.96 PCSK9 monoclonal antibodies which prevent PCSK9 interaction with LDLR have been already approved on the market and been proven to reduce circulating LDL-C levels with good efficacy and tolerance, making PCSK9 emerge as a novel therapeutic target for lowering LDL-C levels recently.
0.94 PCSK9 level and increased hepatic LDLR expression.
0.94 PCSK9 was diminished in 7030B-C5 treated mice compared with HFD group, while LDLR protein level was significantly increased (Fig. 3f), consistent with the dramatically decreased circulating PCSK9 level (Fig. 3b).
0.94 PCSK9 expression and the LDLR level in HFD-induced hyperlipidemic ApoE KO mice with low toxicity and acceptable bioavailability, which may ameliorate abnormal plasma cholesterol metabolism and provide atheroprotection.
0.93 PCSK9/LDLR complex translocates to the endosome-lysosomal compartment where LDLR is degraded.
0.91 PCSK9 have been reported to have pleiotropic effects to affect atherosclerosis lesion size and composition which are independent of ApoE. In our study, it was found that daily oral administration of 7030B-C5 for 12 weeks significantly reduced hepatic and plasma PCSK9 level and increased hepatic LDLR expression.
0.90 LDLR protein expression by reducing plasma PCSK9 in ApoE-deficient mice fed a high-cholesterol diet for 12 weeks.
0.81 PCSK9 monoclonal antibodies (mAbs) alirocumab and evolocumab which were reported to disrupt the PCSK9-LDLR interaction have been approved by the U.S. Food and Drug Administration (FDA).
0.79 PCSK9 and LDLR expression in hepatic cells
0.79 PCSK9 and LDLR expression in hepatic cells.
0.77 LDLR expression, lower plasma cholesterol levels and plaque size was observed by the loss of PCSK9.
0.64 PCSK9 KO in ApoE KO mice revealed little difference in either circulating cholesterol or hepatic LDLR protein levels.
26256967 0.98 PCSK9 either by reducing its expression or by blocking its activity results in the upregulation of the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol.
0.97 LDLR and PCSK9 expression (Fig. 2B).
0.96 LDLR and PCSK9 in a dose-dependent manner (Fig. 2A).
0.96 PCSK9 inhibition is possible augmentation of the cholesterol-lowering effect by statins, which induce simultaneously the expression of PCSK9 and LDLR.
0.95 PCSK9 and its binding motif to the EGF-A domain of the LDLR is well-characterized by several researchers.
0.93 PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependent manner.
0.93 PCSK9-LDLR interaction and increased the amount of LDLR, PCSK9, and the uptake of LDL-cholesterol in vitro.
0.92 Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR.
0.92 PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR.
0.91 PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.
0.91 PCSK9 and the LDLR, thus acting as a modality for hypercholesterolemia treatment.
0.89 PCSK9-dependent manner, although amounts of LDLR and PCSK9 in the liver remained unchanged.
0.86 PCSK9 and the LDLR.
0.84 PCSK9 to the EGF-AB domain of the LDLR in a dose-dependent manner (Supplementary Fig. 1, only online).
0.77 PCSK9 synthesis by siRNA or inhibition of PCSK9 binding to the LDLR by small peptide inhibitors are other promising approaches to the development of hypercholesterolemia therapeutics.
0.57 PCSK9 and the LDLR by performing in silico virtual screening using commercially available chemical libraries and the GOLD algorithm.
0.52 PCSK9 showed positive correlation with the relative inhibition of PCSK9-LDLR binding (rho=0.409, p<0.01), the Dil-LDL uptake (rho=0.313, p<0.01), and the amount of LDLR (rho=0.478, p<0.01).
0.51 PCSK9-LDLR interaction can be a good target for the application of in silico virtual design of small molecules for drug development.
28970592 0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzymatic protein that negatively regulates LDLR.
0.98 PCSK9 participates in regulating the binding of LDLR and PCSK9.
0.97 PCSK9Qbeta-003 vaccine injection was associated with significant up-regulation of sterol-regulatory element-binding protein-2 (SREBP-2), hepatocyte nuclear factor 1alpha (HNF-1alpha), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in LDLR+/- mice.
0.97 PCSK9 binds to the extracellular domain of LDLR, and then mediates internalization and degradation of LDLR, which results in the increase of LDL-C level.
0.97 PCSK9 are associated with autosomal dominant hypercholesterolemia, while loss-of-function mutations are associated with increase in the LDLR surface expression and increased levels of LDL internalization.
0.97 LDLR induced by PCSK9.
0.97 PCSK9 modulates LDL-C levels by a direct interaction between repeat A of the LDLR EGF homology domain and the PCSK9 catalytic domain.
0.96 PCSK9Qbeta-003 vaccine obviously decreased total cholesterol (TC) and up-regulated LDLR expression in both Balb/c mice and LDLR+/- mice.
0.96 PCSK9 activity, which degraded LDLR of hepatocyte.
0.96 PCSK9 level and up-regulated LDLR expression in LDLR+/- mice.
0.95 PCSK9 level and up-regulated LDLR expression in liver.
0.95 PCSK9 by as much as 30%, compared with placebo, making them somewhat self-limiting to further reduce LDL-C. This likely occurs because the transcription factor SREBP-2, that is indirectly up-regulated by statin, activates the Ldlr and Pcsk9 genes.
0.94 PCSK9 in LDLR+/- mice.
0.92 PCSK9Qbeta-003 vaccine obviously decreased plasma total cholesterol in both Balb/c mice and LDLR+/- mice.
0.91 PCSK9, we displayed linear epitopes that were exposed on the surface of the molecule in proximity to the LDLR binding site on the surface of bacteriophage VLPs.
0.83 Ldlr and Pcsk9 genes, and thus makes statin somewhat self-limiting to further reduce LDL-C. To assess the effect of PCSK9Qbeta-003 vaccine on lipid homeostasis in LDLR+/- mice, we evaluated the mRNA expression of SREBP-2, HNF-1alpha and HMG-CoA reductase in liver.
0.81 PCSK9-003 peptide after the second immunization in LDLR+/- mice.
0.72 PCSK9Qbeta-003 vaccination was observed in LDLR+/- mice after the third injection, compared with the control group (15-25% decrease; Fig. 3b,c).
26495026 0.98 Proprotein convertase subtilisin kexin type 9 (PCSK9) modulates LDL-c through post-translational degradation of the LDLR.
0.98 proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades LDLR protein.
0.98 LDLR and PCSK9.
0.98 LDLR and PCSK9.
0.98 PCSK9 protein levels, hepatic S1P KD enhances LDLR protein stability and maintains LDLR protein levels despite the reduction in LDLR mRNA expression.
0.98 PCSK9 regulation of LDLR protein degradation in S1P deficient livers provides an explanation for the discordance in LDLR mRNA and protein expression.
0.98 LDLR and PCSK9.
0.98 LDLR and PCSK9 gene promoters, resulting in less transcription of their mRNAs and reduced plasma PCSK9 protein levels.
0.98 PCSK9 mRNA and protein is more prominent in the fed state, which likely contributes to the increased LDLR protein stability and the maintenance of hepatic LDLR protein levels despite the reduced LDLR mRNA.
0.97 LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9).
0.97 PCSK9 protein after hepatic S1P KD in the fed state provides an explanation for the discordance between LDLR mRNA and protein expression in the fed state (Fig. 2b, c and d).
0.97 LDLR mRNA expression through reducing the SREBPs, and on the other hand, increases LDLR protein levels through down-regulation of PCSK9 expression, again, mediated through the SREBPs.
0.96 PCSK9 levels (Fig. 4d), we believe that the lack of normal S1P-originating production of PCSK9 in such mice is responsible for the discordance in LDLR mRNA (lowered) and protein levels (maintained) seen in the S1P deficient livers (Fig. 2b, d).
0.94 PCSK9 and LDLR regulation under various conditions.
0.93 PCSK9-mediated LDLR protein degradation in the S1P KD mice livers and normalize LDLR protein to that of control mice in the fed state than in fasting conditions.
0.86 PCSK9 concentrations and as a result, liver LDLR protein levels are lower (Fig. 8).
0.59 PCSK9 function is solely responsible for the effect on LDLR protein in the S1P deficient mice.
27171436 0.98 PCSK9 function in sepsis is increased clearance of pathogen lipids, such as LPS, via the LDLR on hepatocytes.
0.98 PCSK9 (p = 0.0003) or LDLR antibody (p = 0.002) (Fig 4D), suggesting that LPS can be bound to LDL and taken up by the LDL receptor.
0.98 PCSK9, a key regulator of LDLR hepatic activity, binds the LDLR and promotes its internalization and degradation in lysosomal compartments in hepatocytes.
0.98 PCSK9 enhances degradation of the closest LDLR family member, VLDLR, and regulates VLDLR protein levels in adipose tissue.
0.98 PCSK9 regulates LPS clearance from the circulation during sepsis by downregulation of hepatocyte LDLR.
0.97 LDLR):receptors downregulated by PCSK9.
0.97 LDLR and PCSK9 regulates LPS clearance from the circulation during sepsis by downregulation of hepatic LDLR.
0.97 PCSK9 is the LDLR.
0.97 PCSK9 inhibition abolishes the effect of Ldlr gene knockout on the physiologic effects of LPS administration in mice.
0.97 PCSK9 further reduced LPS uptake in Ldlr-/- cells (Fig 5A) suggesting that PCSK9 might also act on another LDLR-independent mechanism of LPS uptake.
0.97 Ldlr-/- mice to a greater extent than in wild type mice by Western blot analysis of liver (Fig 5B) thus providing a possible explanation for the effect of PCSK9 on hepatic LPS uptake in Ldlr-/- mice.
0.97 PCSK9, in turn, decreases LDLR density on hepatocytes.
0.97 PCSK9 may be an important regulator of hepatic LDLR-dependent uptake of LPS during sepsis.
0.97 PCSK9 on hepatic LPS uptake in Ldlr-/- mice.
0.95 PCSK9 binds the Low Density Lipoprotein Receptor (LDLR) and promotes LDLR lysosomal degradation so decreased PCSK9 function increases hepatocyte LDLR density.
0.90 PCSK9 further reduced LPS uptake in Ldlr-/- cells.
0.75 LDLR from PCSK9 studies is further uncertain because PCSK9 also binds the Very Low Density Lipoprotein Receptor (VLDLR), ApoE Receptor 2, and others.
27707816 0.98 LDL receptor (LDLR) and PCSK9 expression.
0.98 LDL receptor (LDLR) and PCSK9 gene expression.
0.98 LDLR and PCSK9 expression levels.
0.98 LDLR and PCSK9 at the mRNA level.
0.98 PCSK9 protein levels, and LDLR levels.
0.97 PCSK9 interacts with LDLR on the surface of cells to cause its internalization and degradation.
0.97 Ldlr mRNA reduction and the reduction in plasma PCSK9 led to a nonlinear dose effect of Scap KD on LDLR protein in the liver.
0.95 PCSK9 and LDLR expression.
0.95 PCSK9 should lead to a reduction in LDL-C; however, these effects could potentially be counteracted by the direct effect of SCAP KD on LDLR expression.
0.94 Pcsk9 mRNA KD amplifies the effect of statin on LDLR induction in mice.
0.91 Ldlr and Pcsk9 mRNA levels were both reduced by Scap mRNA KD; however, LDLR protein levels were maintained, probably due to reduced levels of PCSK9 in circulation.
0.90 LDLR and PCSK9 mRNA expression, and PCSK9 is a negative regulator of LDLR, it is critical to determine the effect of targeting SCAP on the balance of LDLR and PCSK9 and how this ultimately affects LDL-C levels in such a model.
0.78 PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey[S]
0.78 Pcsk9 and Ldlr mRNA levels were both reduced by Scap mRNA KD as shown in Fig. 1B, C. Of note, there was a differential effect of Scap mRNA KD on Pcsk9 and Ldlr levels, with Pcsk9 mRNA generally showing a more dramatic reduction relative to Ldlr mRNA (Fig. 1D).
0.66 PCSK9, LDLR, and lipids in mice and rhesus monkeys.
0.54 Pcsk9, and liver LDLR protein in mice
0.52 LDLR, which has been proposed to occur in mice as a result of PCSK9 inhibition, as there was no observed lowering of HDL-C in the PCSK9 siRNA-treated rhesus monkeys.
22992388 0.98 Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice.
0.98 Pcsk9 and Ldlr gene transcription is regulated by sterol regulatory element-binding proteins (SREBPs) .
0.98 Pcsk9, Ldlr is upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice, although to a much lesser degree.
0.98 PCSK9, LDLR expression is controlled by the LXR-Idol axis, in which LXR induces Idol, an E3 ubiquitin ligase that triggers LDLR degradation .
0.97 PCSK9 mRNA expression, resulting in decreased LDLR protein expression .
0.96 PCSK9 and LDLR (Figure 4A) in the infected mice compared to the sham-infected mice.
0.96 PCSK9 levels and a concomitant decrease of LDLR levels in mice.
0.95 PCSK9 and LDLR gene and protein expression in the liver.
0.95 Ldlr gene expression levels in the P. gingivalis-infected mice were 2 times higher compared with the sham-infected mice, the expression of LDLR protein was decreased, possibly because PCSK9 serum levels were increased more than 20 fold in the infected mice.
0.94 LDLR gene expression in the liver and the serum levels of PCSK9.
0.93 PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver.
0.92 PCSK9 and subsequently expression of LDLR in the liver.
0.82 Pcsk9 and Ldlr gene expression was significantly higher in the P. gingivalis-infected mice compared with the sham-infected mice (** P < 0.01, Mann-Whitney U-test).
0.81 PCSK9 and LDLR gene and protein expression in the liver
0.71 PCSK9 or Idol levels and subsequent expression of LDLR and cholesterol levels.
25474576 0.98 PCSK9), a ~74 kDa protein synthesized in the liver interacts with LDLR, leading to its internalization and subsequent lysosomal degradation, thus downregulating the number of cell surface expressed LDLR molecules.
0.98 PCSK9 as a major regulator of the cholesterol homeostasis originates from studies showing that gain-of-function mutations are associated with decrease in the LDLR expression and LDLc internalization, while loss-of-function mutations are associated with increase in the LDLR surface expression and increased levels of LDL internalization.
0.98 PCSK9-LDLR interaction leads to up-regulation of LDLR in hepatocytes, thus promoting plasma cholesterol uptake from the blood circulation .
0.98 PCSK9 antibodies target and inhibit the PCSK9-LDLR interaction ( Figure 1C ), and subsequently upregulate LDLR ( Figure 1D ) thereby influencing the plasma levels of all ligands able to bind LDLR.
0.97 LDLR and apolipoprotein B (ApoB), the gene encoding PCSK9 constitutes a third locus involved in the development of the autosomal dominant hypercholesterolemia (ADH).
0.97 LDLR, but also PCSK9, causing the so-called paradox of statin treatment: although they induce a beneficial increase in LDLR, they also increase PCSK9, thus leading to LDLR degradation.
0.96 PCSK9 and inhibit its interaction with LDLR.
0.93 PCSK9 vaccine should ultimately prevent the binding of PCSK9 to the LDLR.
0.93 Ldlr +/- mice provided additional confirmation of the powerful effect of the peptide-based anti-PCSK9 vaccine, in particular on LDLc.
0.90 PCSK9 vaccine significantly lowers the LDLc in Ldlr +/- male and female mice upon 4 immunizations.
0.87 PCSK9-LDLR interaction.
0.85 PCSK9-LDLR interaction which consequently resulted in LDLR up-regulation.
0.76 PCSK9-inhibiting approaches have been proposed, including gene silencing and inhibition of PCSK9-LDLR binding by monoclonal antibodies, small peptides or adnectins.
0.67 PCSK9-LDLR interaction, the presence of at least one allele of the receptor is essential in order to evaluate the effect of the anti-PCSK9 vaccine on the LDLR and thus on LDLc.
26023080 0.98 PCSK9 is a secreted protein which binds to the extracellular domain of the LDL receptor and targets it for degradation .
0.98 LDL receptor in vitro in a PCSK9-dependent manner.
0.98 LDLR is complex, and suggest that in vivo, insulin may act through PCSK9-independent mechanisms to increase LDLR protein expression.
0.97 Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds the low density lipoprotein (LDL) receptor and targets it for degradation, has emerged as an important regulator of serum cholesterol levels and cardiovascular disease risk.
0.97 LDLR protein was blunted by knockdown of PCSK9 (Fig. 2B).
0.97 LDLR synthesis and degradation, and is consistent with our in vitro data showing increased Pcsk9 and Ldlr mRNA in the presence of insulin.
0.96 PCSK9 in insulin deficient states are generally not associated with an increase in LDLR protein; indeed, in LIRKO mice re-fed a carbohydrate diet for 6-12 hours, or LIRKO mice fed a Paigen diet, LDLR protein is decreased.
0.95 PCSK9 has emerged as an important regulator of the LDL receptor and a novel therapeutic target.
0.93 PCSK9 in regulating the LDL receptor, a great deal of effort has recently been placed on producing inhibitors of PCSK9 for therapeutic use.
0.93 PCSK9 and inducible degrader of the LDLR (IDOL) promote the degradation of the LDLR.
0.93 PCSK9, decreased Pcsk9 and Ldlr mRNA levels, and normal LDLR protein levels (Fig. 3A-C, 3E).
0.93 Pcsk9 and Ldlr mRNA in both control and LIRKO mice.
0.86 LDLR protein than controls, despite the fact that Pcsk9 levels were lower.
0.85 Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an important regulator of the LDL receptor.
23344002 0.98 proprotein convertase subtilisin/kexin type 9 (PCSK9) in low-density lipoprotein receptor (LDLR) protein regulation.
0.98 PCSK9 messenger RNA (mRNA) levels concomitantly with increases in LDLR protein levels.
0.98 PCSK9 forms a stable complex with LDLR in lysosomes, which disturbs the recycling of LDLR to reduce LDL uptake.
0.97 PCSK9 directly binds to an extracellular part of the LDLR.
0.97 PCSK9 would be a pivotal regulator of LDLR and an attractive target for lipid-lowering therapy, although some molecular functions of PCSK9 remain unknown.
0.97 PCSK9 mRNA and induces an increase in LDLR protein levels both in vitro and in vivo.
0.97 LDLR in P900SL-treated cells were increased in a dose-dependent manner, showing the inverse relationship between PCSK9 and LDLR protein levels.
0.96 LDLR-PCSK9 complex is transported from the cell surface to the endosomal system for digestion.
0.93 PCSK9 in LDLR regulation.
0.86 PCSK9 mRNA expression was suppressed and the hepatic LDLR protein was increased accompanied by AON treatment with relatively large deviations (Figure 7b,c).
0.84 PCSK9 mRNA were previously reported by Gupta et al. They achieved the silencing of PCSK9 concomitantly with the upregulation of hepatic LDLR in female mice.
0.72 LDLR protein, and PCSK9 mRNA levels after treatment of P901SL and P901SL.
0.52 LDLR mRNA expression was independent of PCSK9 inhibition.
29438441 0.98 PCSK9 synthesized in the liver interacts with the LDLR, thus leading to its internalization and subsequent lysosomal degradation and the subsequent down-regulation of the number of cell-surface LDLR molecules.
0.98 PCSK9 results in a sex- and tissue-specific subcellular distribution of the LDLR and VLDLR, which is determined by 17beta-estradiol levels.
0.98 PCSK9 antibodies produced by our selected vaccine target inhibited PCSK9-LDLR internalization and up-regulated cell-surface LDLR expression, thereby influencing the plasma levels of VLDL particles.
0.97 PCSK9 therapeutic vaccines have been found to decrease LDL cholesterol levels via inhibition of PCSK9-LDLR interactions.
0.97 PCSK9 C-terminal domain contributes to inhibition of LDLR function primarily via effects on the cellular uptake of PCSK9 and LDLR complex without altering the binding affinity for LDLR.
0.95 LDLR epidermal growth factor-like repeat A domain binds exclusively to the catalytic domain of PCSK9.
0.94 PCSK9-LDLR interaction.
0.94 PCSK9 vaccine induced long-lasting anti-PCSK9 antibody production, up-regulated cell surface LDLR expression and significantly decreased VLDL cholesterol and CM in ApoE-deficient mice.
0.91 PCSK9's interaction with the LDLR and internalization, and an increase in LDLR expression was expected.
0.85 PCSK9-LDLR internalization using vaccination would result primarily in a decrease in VLDL cholesterol.
0.83 proprotein convertase subtilisin/kexin type 9 (PCSK9) in the metabolism of low-density lipoprotein (LDL) and the LDL receptor (LDLR) and the verified safety of PCSK9 inhibition has led to the development of PCSK9 inhibitors.
0.79 PCSK9 peptide vaccine to increase the levels of plasma PCSK9 and the expression of cell-surface LDLR, and to improve plasma lipoprotein profiles.
0.53 PCSK9 was crystallized in a complex with the epidermal growth factor-like repeat A domain of the LDLR at acidic and neutral pH values.
30671557 0.98 Pro-protein convertase subtilisin/kexin type 9 (PCSK9), a secreted serine protease, regulates serum low-density lipoprotein (LDL) cholesterol levels by targeting the degradation of LDL receptor (LDLR) in the liver.
0.98 Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted serine protease that degrades LDLR in the liver and thus regulates serum LDL-C levels.
0.98 PCSK9 acts as a post-transcriptional regulator of LDLR and has been identified as a major determinant of plasma LDL-C levels.
0.98 LDLR expression, which may further affect lipid homeostasis and thus regulate PCSK9 expression.
0.98 PCSK9 levels and concomitantly decreased expression of Ldlr and Srebp2 in the liver.
0.98 PCSK9 and LDLR is regulated by SREBPs, a feedback-regulated cholesterol synthesis mechanism may enhance the production of PCSK9 via an increase in LDLR expression.
0.97 LDLR expression precede an increase in the serum PCSK9 level in the context of an infectious disease such as periodontitis.
0.97 LDLR protein while concomitantly increasing hepatic PCSK9 mRNA expression.
0.96 LDLR is independent of the change in serum PCSK9 levels in response to infection.
0.91 PCSK9 and LDLR were not directly promoted by P. gingivalis (Fig. 4A and B).
0.91 LDLR but not of PCSK9 (Fig. 4E and F).
0.82 PCSK9 was not significantly promoted but that of LDLR was significantly promoted in dose-dependent manner (Fig. 4C and D).
0.62 PCSK9, the ability of P. gingivalis to promote PCSK9 and LDLR gene expression in vitro was analyzed in the hepatic cell line HepG2.
18638454 0.98 PCSK9 binds to the LDL receptor on the plasma membrane leading to the redistribution of LDL receptors from the cell surface to lysosomes and their ultimate degradation.
0.98 PCSK9 in the liver thereby decreasing hepatic LDL receptor protein levels resulting in increases in circulating LDL levels.
0.97 Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation.
0.97 PCSK9 expression leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense.
0.97 proprotein convertase subtilisin kexin 9 (PCSK9), a serine protease, plays an important role in regulating hepatic LDL receptor levels.
0.97 PCSK9 plays an important role in regulating hepatic LDL receptor protein levels and consequently serum cholesterol levels.
0.97 PCSK9 from a transgenic overexpressor mouse reduced LDL receptor levels in the liver of the paired nontransgenic mouse.
0.97 PCSK9 expression one would also expect that LDL receptor mRNA levels would also be increased as SREBP-2 is well known to be a potent stimulator of LDL receptor gene expression.
0.94 PCSK9 lowers LDL receptor levels.
0.94 LDL receptor mRNA and PCSK9 mRNA (at 8 hours PCSK9 expression is increased 2-3 fold while LDL receptor expression is decreased by 50%) providing further evidence suggesting that increases in SREBP activity are not likely to underlie the changes in PCSK9 expression.
0.87 PCSK9 and LDL receptor expression.
28178673 0.98 PCSK9 is a secreted serine protease that regulates the post-transcriptional degradation of the low density lipoprotein (LDL) receptor (LDLR) to reduce cholesterol uptake.
0.98 PCSK9-induced degradation of LDLR results in reduced intracellular cholesterol uptake and increased serum LDL-cholesterol levels.
0.98 PCSK9 expression and inhibits LDLR expression at the post-translational level.
0.98 PCSK9 knockdown rescued the cholesterol-lowering and anti-proliferative effects of acRoots, suggesting that PCSK9 has a key role in cholesterol metabolism and that PCSK9 and LDLR expression are inversely correlated.
0.98 PCSK9 and LDLR transcription through binding to functional sterol regulatory elements in the promoters of these genes.
0.97 PCSK9 expression and increased LDLR expression have been observed in HCC tissues, which may provide a constant supply of cholesterol in the HCC microenvironment.
0.97 PCSK9 expression and reduces LDLR levels.
0.97 PCSK9 expression, which decreases LDLR expression at the post-transcriptional level, inhibits LDL uptake, lowers the total intracellular cholesterol concentration, and suppresses cell viablity in LM3 cells (Figure 7L).
0.95 PCSK9 overexpression further decreased acRoots-mediated LDLR expression, Dil-LDL uptake, the total cholesterol concentration, and cell viability (Figure 5B, 5C, 5D and 5E).
0.89 LDLR and surface LDLR protein expression by acRoots was significantly rescued by PCSK9-siRNA, while the LDLR mRNA level was still slightly up-regulated by acRoots (Figure 6D, 6E, 6F, and 6G).
0.80 LDLR mRNA level concomitant with up-regulation of PCSK9 expression in acRoots-treated LM3 cells (Figure 4C).
22962999 0.98 proprotein convertase subtilisin/kexin type 9 (PCSK9), which enhances intracellular degradation of LDLR in lysosomes.
0.98 LDLR expression through up-regulation of hepatic expression of PCSK9 mRNA.
0.98 PCSK9, a member of the subtilisin family of serine proteases, has been shown to induce intracellular degradation of LDLR.
0.98 LDLR post-transcriptional regulation by proprotein convertase subtilisin/kexin type 9 (PCSK9) and LXR/inducible degrader of LDLR (IDOL) signaling pathways.
0.98 PCSK9 binds to the EGF-A extracellular domain of LDLR and subsequently triggers its intracellular degradation in lysosomes.
0.98 LDLR degradation through PCSK9 mRNA up-regulation in the SREBP2 signaling pathway.
0.98 LDLR degradation is promoted by fucoxanthin through up-regulation of PCSK9 and leads to increased non-HDL-cholesterol levels.
0.97 LDLR expression was due to PCSK9-associated LDLR degradation induced by fucoxanthin.
0.93 PCSK9 mRNA involved in LDLR degradation
0.92 PCSK9 overexpression in mice reduced LDLR levels and increased non-HDL-cholesterol levels.
27995077 0.98 PCSK9 binds to LDLR at the cell surface, gets endocytosed with it, prevents its recycling to the surface, rerouting it to lysosomes where it is degraded.
0.98 PCSK9-LDLR opposing tandem regulates plasma cholesterol, novel implications of this tandem in other physiological pathways are emerging, most dramatic among them being the clearance of toxins following bacterial infection.
0.97 Low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are opposing regulators of plasma LDL-cholesterol levels.
0.97 PCSK9 reduces the amount of LDLR at the surface of hepatocytes, resulting in diminished clearance of blood LDL-C; and vice versa.
0.96 PCSK9 and cholesterol levels in plasma, due to genetic variations leading to reduced secretion of PCSK9 associated with greater LDLR-degrading activity.
0.93 PCSK9 protein deficiency associated with enhanced LDLR-degrading activity.
0.86 PCSK9 is more efficient at degrading LDLR than its B6 homolog, presumably because of the differences identified in their primary structures.
0.83 PCSK9 (Fig. 2Aa, P < 0.001) and 1.25-fold more LDLR (Fig. 2Ab, P < 0.01).
0.79 LDLR (2.5-fold) would be consistent with the lower plasma level of PCSK9 (i.e. reduced PCSK9-mediated degradation of the receptor),
0.58 PCSK9 and more LDLR in liver.
29803939 0.98 convertase subtilisin/kexin type 9 (PCSK9) are also associated with familial hypercholesterolemia, reflecting the ability of PCSK9 to reduce cell-surface LDLR expression on hepatocytes.
0.98 PCSK9 to the EGF-A domain of the LDLR allows formation of a PCSK9-LDLR complex, which undergoes endocytosis and lysosomal degradation.
0.98 PCSK9 prevents LDLR recycling back to the plasma membrane, thus reducing LDLR receptor content.
0.98 PCSK9-LDLR complex formation.
0.98 PCSK9 from cell surface HSPGs and prevent its presentation to the LDLR.
0.97 PCSK9-mediated lowering of hepatic LDLR expression.
0.96 LDLR protein expression (without affecting LDLR mRNA expression) and greater LDL uptake, whereas GPC3 overexpression had the opposite effect, i.e. less PCSK9 mediated degradation of LDLR.
0.96 PCSK9 levels and increased hepatic LDLR expression.
0.83 PCSK9 heparin-binding site do not affect PCSK9-LDLR interactions, but these antibodies have the same therapeutic effects in mice as the PCSK9 monoclonal antibody, Evolocumab, which targets the binding of PCSK9 binding to LDLR.
0.80 LDLR expression (statins and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) or reduce cholesterol absorption (ezetimibe).
23862065 0.98 LDLr regulation was significantly bolstered by the more recent discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, a serine endoprotease that promotes degradation of the LDLr protein.
0.98 PCSK9 shares a common transcriptional regulatory pathway with the LDLr through SREBP2.
0.98 PCSK9 and LDLr mRNA (Figures 3(a) and 4(a), resp.), likely the result of a reduction in hepatic cholesterol (Figure 2(b)) and subsequent induction of nuclear SREBP2 protein abundance (Figure 5(b)).
0.98 PCSK9 and the LDLr are transcriptionally upregulated following SREBP2 cleavage at the endoplasmic reticulum and subsequent nuclear translocation.
0.97 PCSK9 is inversely related to LDL particle clearance, it is considered a potentially important biomarker of cardiovascular disease risk, intimately reflective of hepatic SREBP2 expression and LDLr activity.
0.97 PCSK9 protein is composed of a prodomain, a catalytic domain that binds to the EGF-A domain of the LDLr and a C-terminal domain that interacts with cell-surface proteins.
0.96 PCSK9 in regulating hepatic LDLr uptake and the recent report of increased fractional LDL clearance in response to exercise, there are emerging questions regarding the potential role of exercise training as a modulator of PCSK9 metabolism.
0.96 PCSK9 concentrations and enhances the hepatic mRNA expression of SREBP2, LDLr, and PCSK9.
0.89 PCSK9 on LDLr expression and activity in extrahepatic tissues cannot be ruled out as contributing to the observed cholesterol reductions in the exercised animals.
26413878 0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the low-density lipoprotein receptor (LDL-R).
0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic secretory protein that acts as a negative regulator of LDL-R by blocking the recycling of the receptor to the cell surface.
0.98 PCSK9 in plasma binds to the extracellular domain of LDL-R and mediates its internalization and degradation, thus increasing circulating levels of LDL-C by preventing its uptake.
0.98 PCSK9 is unable to degrade LDL-R, and several naturally occurring gain-of-function mutations in this region may therefore decrease cleavage and hence decrease inactivation of PCSK9.
0.96 PCSK9 by as much as 30% as compared to placebo, making them somewhat self-limiting in their ability to further reduce LDL-C. This likely occurs because the transcription factor SREBP-2, that is indirectly upregulated by statins, activates the Ldlr and Pcsk9 genes.
0.95 PCSK9 have been shown to block PCSK9 binding to LDL-R (PMID: 19196236).
0.94 PCSK9 bound to LDL-R as a guide, we engineered VLP-based vaccines that targeted five regions of PCSK9 that were predicted to be involved in LDL-R binding (Figure 1).
0.93 PCSK9 in the experimental group was largely due to the presence of immunoglobulin-bound PCSK9, which likely have decreased plasma clearance compared to free PCSK9 but are ineffective in their interaction with LDL-R. These data also provide evidence that IgG elicited by vaccination binds to PCSK9 in vivo.
0.81 PCSK9 and observations of the metabolic consequences of gain-of-function and loss-of-function mutations have demonstrated that blocking its ability to bind LDL-R is sufficient to neutralize its activity and results in significantly lower circulating LDL-C. These features make PCSK9 an ideal candidate for mAb-based therapies and clinical trials of several candidates have been highly promising.
25139399 0.98 PCSK9 is responsible for targeting the LDL receptor (LDLR) for lysosomal degradation in the liver by preventing recycling of the receptor to the cell membrane after internalization of the LDL-bound LDLR.
0.98 PCSK9 interacts with the LDLR on the cell membrane, after which the LDLR-PCSK9 complex is internalized and travels through the endosome to the lysosome for degradation.
0.98 LDLR after statin treatment is accompanied by an upregulation of PCSK9, which in turn promotes LDLR degradation.
0.97 LDLR-/- mice with or without expression of PCSK9 revealed a direct relationship between PCSK9 and atherosclerosis development, mainly mediated via the LDLR, and suggests that PCSK9 inhibition will be beneficial in reducing atherosclerosis.
0.96 LDLR-deficient mice expressing no, normal, or high PCSK9 levels, suggesting that PCSK9 modulates atherosclerosis mainly via the LDLR.
0.95 PCSK9 increased plasma LDL-C levels, which was associated with decreased hepatic LDLR protein, although LDLR mRNA levels were unaffected.
0.95 PCSK9 have decreased plasma LDL-C as a result of increased hepatic LDLR levels.
0.89 ldlr mutations and familial defective apoB100 caused by apob mutations, autosomal dominant hypercholesterolemia can be caused by gain-of-function mutations in the pcsk9 gene, now commonly referred to as FH3.
27358438 0.98 LDL receptor is regulated by both the E3 ubiquitin ligase Idol (Inducible degrader of the LDL receptor) and PCSK9.
0.97 Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged over the past decade as a post-transcriptional regulator of the LDL receptor, and several studies have suggested an association between PCSK9 and renal function.
0.97 PCSK9 that were correlated with reduced levels of LDL receptor protein and an increased proportion of ApoB-associated cholesterol.
0.97 LDL receptor, a target of PCSK9, participates in the clearance of PCSK9 from the plasma.
0.96 PCSK9 binding to and uptake by the LDL receptor.
0.95 LDL receptor protein observed in Flox mice was blunted in PCSK9 L-KO mice (Figure S4B).
0.74 PCSK9 clearance could be secondary to the decrease in LDL receptor and increase in LDL cholesterol.
0.73 LDL receptor protein, though Pod-ATTAC livers showed no changes in Ldlr, Idol, or Pcsk9 mRNA (Figure 3E, F, H).
29162602 0.98 LDLR and PCSK9 message and protein in rosuvastatin-treated SR-B1-/-/apoE-/- mice are consistent with the known coordinate upregulation of LDLR and PCSK9 gene expression by inhibition of cholesterol biosynthesis, and the ability of PCSK9 itself, secreted by the liver, to promote the degradation of LDLR in hepatocytes (though we noted no differences in the levels of another reported target of PCSK9, LRP-1; Figure I in the online-only Data Supplement).
0.98 LDLR and PCSK9 transcripts in livers of rosuvastatin-treated SR-B1-/-/apoE-/- mice (Figure 1N and 1O), consistent with the known effects of statin-induced inhibition of cholesterol biosynthesis and activation of the SREBP-2 (sterol regulatory element-binding protein 2) transcription factor in the liver.
0.98 PCSK9 that is either secreted by hepatocytes, or acting intracellularly, can bind to the LDLR and trigger its degradation, reducing LDLR protein levels thereby attenuating the effects of SREBP-2-mediated upregulation of LDLR gene expression, and attenuating statin dependent cholesterol lowering.
0.97 PCSK9 protein while reducing LDLR protein in livers and that treatment of hyperlipidemic mice with rosuvastatin increased PCSK9 mRNA in liver and protein in plasma.
0.96 PCSK9 (proprotein convertase subtilisin/kexin type-9) and LDLR (low-density lipoprotein receptor) message, increased plasma PCSK9 protein but decreased levels of hepatic LDLR protein and increased plasma total cholesterol associated with apoB (apolipoprotein B) 48-containing lipoproteins.
0.96 LDLR (LDL receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9) gene expression but reduced levels of hepatic LDLR protein and increased plasma cholesterol associated with VLDL-sized lipoprotein particles.
0.78 PCSK9 protein in plasma (Figure 1P), we detected a >50% reduction in the amount of LDLR protein in liver membranes from the same rosuvastatin-treated SR-B1-/-/apoE-/- mice (Figure 1L and 1M).
0.63 PCSK9 or hepatic LDLR protein contribute to the observed increases in apoB48, which is not a ligand of LDLR.
32051723 0.98 PCSK9) is an important modulator of cholesterol haemostasis through controlling the clearance of the plasma LDL-C from the bloodstream via regulation of the liver's LDL receptor (LDLR).
0.98 PCSK9 and suppress its binding to LDLR, thereby leading to the inhibition of PCSK9 function.
0.97 PCSK9, in which the LDLR-dependent effect of PCSK9 was affected, while genetic mutations possessing LDL-lowering variants can modulate intracellular activity of PCSK9 beyond its regulatory effect on LDLR, such as regulation of cell cycle and apoptosis.
0.96 PCSK9-LDLR binding assay revealed that in the presence of plasma anti-PCSK9 antibodies, interaction between murine PCSK9 and LDLR was inhibited.
0.96 PCSK9 function through suppression of PCSK9/LDLR interaction via induction of antiPCSK9 antibodies in vaccinated BALB/c mice.
0.89 PCSK9 binding to LDLR by 50%, compared with the plasma from the control group (Figure 5 D).
0.80 PCSK9-LDLR binding inhibition by vaccine-induced PCSK9 antibodies
0.77 PCSK9 binding to LDLR by 50%, when compared with plasma sample of control group.
23580231 0.98 LDLR levels are up-regulated in SEC24A-deficient cells as a consequence of specific dependence of PCSK9, a negative regulator of LDLR, on SEC24A for efficient exit from the ER.
0.98 PCSK9, a circulating factor that negatively regulates cell surface LDL receptor expression.
0.98 LDLR protein levels by decreasing circulating PCSK9.
0.98 LDLR levels are regulated by intracellular factors such as the E3 ligase IDOL and circulating PCSK9.
0.98 PCSK9, a circulating regulator of cell surface LDL receptor.
0.98 LDLR levels are up-regulated in SEC24A deficient mice as a consequence of a specific dependence of PCSK9 on SEC24A for efficient exit from the ER.
0.95 Low Density Lipoprotein Receptor (LDLR), HMG-CoA reductase, and PCSK9, remained unchanged by mRNA-seq and qPCR, though SCD1 was decreased by ~50% in Sec24agt/gt mice (Figure 5D), as observed by mRNA-seq (FDR < 3 x 10-13).
25023731 0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL) negatively regulate LDLR protein and could dampen AAV encoded LDLR expression.
0.98 PCSK9 to bind and sequester LDLR in an intracellular compartment that increases receptor degradation.
0.98 LDLR expression is subject to multiple pathways of regulation; of these, regulation by PCSK9 has emerged as the leading candidate for development of second generation lipid lowering drugs and several clinical studies are underway to augment LDLR expression by interfering with PCSK9 mediated degradation of the receptor.
0.95 PCSK9 and led to a significant decrease in serum cholesterol; whereas, wild-type LDLR was less efficient and more readily degraded by PCSK9.
0.92 LDLR expression were also bolstered by reports that subjects with naturally occurring loss-of-function mutations in PCSK9 and IDOL have lower LDL-C levels but have no disease associated with these mutation; therefore, avoiding LDLR degradation by these regulatory pathways should be considered to be safe and potentially helpful in improving gene therapy for hoFH.
0.90 PCSK9-resistant LDLR cDNA may be a more effective transgene for gene therapy for homozygous FH.
28262545 0.98 PCSK9 as an extracellular protein responsible for the internalization and degradation of surface LDLR in hepatocytes.
0.98 PCSK9 is induced by statins, and activates a negative feedback loop that controls LDLR expression and consequently restrains the efficacy of statins.
0.95 LDLR and PCSK9 and the ability of the derived iHeps to increase LDL uptake in vitro upon treatment with statins.
0.92 LDLR degradation pathway (besides PCSK9) may provide alternative therapeutic avenues for hypercholesterolemia.
0.89 LDLR, including gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9).
0.77 LDLR or PCSK9 and have tested the ability of the derived iHeps to mimic the disease phenotype and respond to statins in vitro.
28808191 0.98 PCSK9, which is synthesized and secreted by hepatocytes, binds the LDLR on its ligand binding domain, leading to the internalization of the LDLR:PCSK9 complex and their subsequent degradation in the lysosome, rather than allowing LDLR's recycling back to the plasma membrane.
0.98 PCSK9 is regulated by SREBP2, which can lead to a confounding effect of low cellular cholesterol levels leading to upregulation of HMGCR, LDLR (increasing cellular cholesterol levels through endogenous and exogenous pathways) and upregulation of PCSK9 (decreasing cell surface levels of LDLR).
0.98 PCSK9 expression is the primary regulator of LDLR cell surface expression.
0.97 PCSK9 is the main regulator of hepatocyte LDLR expression levels, not SREBP2.
0.96 LDLR is regulated by a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9)[ , , - , ].
0.86 PCSK9 may have the most profound effect on LDLR but not HMGCR.
31666640 0.98 LDL receptor (LDLR) expression through a complementary mechanism of increased stability of the transcript and suppression of HNF1alpha-mediated PCSK9 gene transcription.
0.98 LDLR through two complementary mechanisms of prolonging LDLR transcript and simultaneously inhibiting the transcription of PCSK9, the degrader of LDLR protein.
0.98 LDLR expression, it has been reported that in mice, adenoviral mediated over expression of TRIB1 increased liver LDLR expression due to reduced plasma PCSK9 levels.
0.93 Ldlr as well as Pcsk9 remained unchanged.
0.92 LDLR, PCSK9 and TRIB1 are all important regulators of circulating LDL-C and the CVD risk, their concurrent regulations by the natural lipid lowering compound BBR warrant further investigations.
0.82 LDLR and PCSK9 mRNA expression, the siRNA-mediated depletion of TRIB1 recaptured the results of adenovirus-mediated knockdown without affecting basal and BBR-regulated expressions (Fig. 8G,H).
31870234 0.98 PCSK9 (proprotein convertase subtilisin/kexin type 9) is a hepatic enzymatic protein that negatively regulates low density lipoprotein receptor (LDLR).
0.97 PCSK9 binds to the extracellular domain of LDLR, and then mediates internalization and degradation of LDLR, which results in the increase of low-density lipoprotein cholesterol (LDL-C) level.
0.95 PCSK9 was reported to affect the activity of other receptors beyond LDLR, such as CD36, VLDLR, apolipoprotein E receptors, and LDLR-related protein 1.35, 36 Our results showed that the PCSK9Qbeta-003 vaccine significantly increased the expression of LDLR and VLDLR.
0.86 PCSK9 inhibitors on renal function and fibrosis is worth exploring.30, 31 Significantly, in addition to the decrease of LDL-C level, the PCSK9Qbeta-003 vaccine further ameliorated renal lipid accumulation and renal fibrosis, and then improved renal function in the LDLR+/- UUO and L-NAME mice.
0.69 PCSK9Qbeta-003 vaccination was observed in LDLR+/- mice after the third injection (Figure 1D through 1F).
0.60 PCSK9 (proprotein convertase subtilisin/kexin type 9) Qbeta-003 vaccine significantly improved renal lipid accumulation and attenuated the development of renal fibrosis induced in low-density lipoprotein receptor +/-
32039393 0.98 LDLR, secreted PCSK9 was recently shown to promote the degradation of several other receptors known to be involved in the uptake of lipid from the circulation into the liver, such as the very low-density lipoprotein receptor (VLDLR), LDLR-related protein-1, the apolipoprotein E (ApoE) receptor-2 and CD36.
0.97 LDLR, CD36 and the VLDLR, changes in hepatic ABCA1 expression in Pcsk9-/- mice likely occurred as a result of increased mRNA transcript expression (Fig. S5B).
0.96 PCSK9 and its ability to induce the degradation of the low-density lipoprotein (LDL) receptor (LDLR) once secreted from the liver, firmly positioned PCSK9 as a target for the management of CVD.
0.96 LDLR, VLDLR and CD36 expression in the livers of Pcsk9-/- mice compared to controls.
0.95 PCSK9 to interact with CD36 differs from its LDLR-binding domain, it remains possible and even likely that such antibodies may also reduce CD36 expression as a byproduct of increasing the circulating pool of PCSK9.
0.83 PCSK9 expression was inversely correlated with LDLR and CD36 expression.
24252756 0.98 PCSK9 positively regulates APOB concentration (Figure 2(5)) and inhibition of PCSK9 leads to an increase of LDLR (Figure 2A(6)) and APOB-containing LDL particles are more rapidly cleared.
0.98 PCSK9-mediated HDL regulation is mainly through low-density lipoprotein (LDLR).
0.98 LDLR through PCSK9 cleavage.
0.97 PCSK9 influences glucose and lipoprotein metabolisms by regulating insulin and LDLR receptor degradation.
0.51 LDLR by PCSK9 inhibition and overexpression remains unclear and additional studies would be needed to address this observation.
25320235 0.98 LDLR in mice and a PCSK9-resistant variant of LDLR in humans reduced the effect of PCSK9, implicating the LDLR in this pathogen lipid clearance pathway.
0.97 Ldlr-/- mice, we found that the effects of PCSK9 inhibition on activity and body temperature were abolished (table S1), indicating that PCSK9 altered these physiological responses to LPS injection via the LDLR.
0.97 PCSK9 function increases pathogen lipid clearance via the LDLR and thereby decreases the inflammatory response and improves outcomes in sepsis in both mice and humans.
0.89 PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9.
0.89 LDLR rs688 results are not conclusive, but together with murine Ldlr-/- observations and with the knowledge that the primary effect of PCSK9 is on the LDLR with respect to cholesterol clearance, our observations suggest that the effect of PCSK9 in sepsis is mediated via the LDLR.
25600226 0.98 PCSK9 levels are doubled resulting in reduced LDLR expression and an increase in LDL-C; thus annexin A2 is viewed as endogenous inhibitor of PCSK9.
0.98 PCSK9 overexpression increases LDL-C concentration in mice and accelerates the development of atherosclerosis, the latter being absent in LDLR-knockout mice.
0.97 PCSK9 into mice results in increased LDL-C, as LDLR are downregulated.
0.94 PCSK9-knockout mice carry more LDLR and less insulin in the pancreas, leading to hyperglycemia and glucose intolerance.
0.71 PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice.
26847647 0.98 PCSK9 is a serine protease that binds to the epidermal growth factor-like repeat A on the LDL receptor.
0.98 LDL receptor, PCSK9 initiates internalization and lysosomal degradation of the LDLR/PCSK9 complex, resulting in decreased LDL receptors on the surface of hepatocytes and increased LDL-C concentrations in blood.
0.97 PCSK9 diminishes LDL receptor protein and function, causing an Ldlr knockout phenotype in mice.
0.97 Pcsk9-deficient mice showed reduced plasma cholesterol levels by increasing LDL receptor protein expression in liver and accelerating the clearance of circulating cholesterol.
0.97 Ldlr-deficient mice, overexpression of PCSK9 did not regulate the circulating cholesterol levels, aortic accumulation of cholesteryl esters and atherosclerotic plaque size, indicating that the pro-atherosclerotic effect of PCSK9 is mediated mainly through its action on the LDL receptor.
28301372 0.98 proprotein convertase subtilisin/kexin type 9 (PCSK9) directs LDLR via the endocytic pathway to the lysosomes and prevents the recycling of LDLR (Fig. 1).
0.98 PCSK9, ubiquitin ligase inducible degrader of the LDLR (IDOL) stimulates the proteolysis of LDLR in a variety of tissues including the brain (reviewed in) (Fig. 1).
0.97 LDLR function has been identified, resulting in the development of new therapies, such as PCSK9 inhibitors, to lower plasma cholesterol levels.
0.96 PCSK9 and IDOL-mediated LDLR degradation pathways make use of the endocytic system and it would be therefore informative to assess, whether the CCC and WASH complexes also participate in the sorting of LDLR to lysosomes.
0.93 LDLR is sent to the lysosomes for proteolysis, which is mediated by PCSK9 and/or IDOL.
28637178 0.98 PCSK9, mainly synthesized in the liver, binds to the LDLR and enhances its degradation, thereby modulating cholesterol levels of circulating apoB-containing lipoproteins (i.e., VLDL and LDL).
0.97 PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis.
0.97 PCSK9, LDLR expression and its activity are increased, leading to plasma VLDL- and LDL-cholesterol lowering.
0.97 LDLR, but also increase PCSK9, which leads to LDLR degradation, thus causing a negative feedback response that attenuates the statins' lipid effects.
0.97 PCSK9 plays a fundamental role in LDL metabolism through the binding and degradation of LDLR.
29404461 0.98 LDLR and PCSK9 mRNAs promote opposing forces on LDLR protein expression, concomitantly decreasing its synthesis while increasing its stability.
0.97 proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased.
0.96 LDLR protein expression, decreases secreted PCSK9, and increases uptake of LDL particles.
0.96 LDLR, which enhances the clearance of plasma lipoproteins; however, it also up-regulates PCSK9, which promotes LDLR degradation.33, 34 Thus, the efficacy of statins is self-limiting and determined through the establishment of a new steady state that represents the net effect of opposing factors.
0.85 PCSK9 that have significant LDL-C lowering effects, represents an alternative choice for combination therapy as they would specifically block the PCSK9 effect of SREBP up-regulation while maintaining the increased expression of LDLR mRNA.35, 36 However, these agents would not inhibit HMGCR mRNA expression.
29903737 0.98 PCSK9 that recognizes the ectodomain of the LDLR and the related receptors VLDLR (very low-density lipoprotein receptor) and APOER2 (apolipoprotein E receptor 2), IDOL recognizes the intracellular tail of these receptors, and acting as an E3 ubiquitin ligase promotes their ubiquitylation and subsequent lysosomal degradation.
0.97 LDLR levels are associated with a higher incidence of DM2, as seen, for example, in statin-treated individuals and in mice lacking Pcsk9.
0.96 PCSK9 is known to potently regulate hepatic LDLR but less so in the adrenal gland.
0.93 Pcsk9:a secreted factor that like Idol targets the LDLR:do have an altered postprandial response.
0.80 PCSK9 (proprotein convertase subtilisin/kexin type 9):a novel cholesterol-lowering strategy that is also based on increasing the level of the LDLR:has not been associated with increased DM2 yet.
24916110 0.98 PCSK9 functions to downregulate LDLR; consistent with this relationship, the CRISPR-Pcsk9 mice had higher levels of LDLR protein than the control groups of mice (Figure 2D).
0.97 LDL receptor (LDLR), PCSK9 was originally identified as the cause of autosomal dominant hypercholesterolemia in some families, with gain-of-function mutations in the gene driving highly elevated LDL-C levels and premature CHD.
0.93 Pcsk9 gene in vivo with high efficiency and result in decreased circulating PCSK9 levels, increased hepatic LDLR levels, and decreased plasma cholesterol levels.
0.78 PCSK9 levels, increased hepatic LDL receptor levels, and decreased plasma cholesterol levels (by 35%-40%) in the blood.
25544176 0.98 LDLR, due not only to direct degradation of LDLR but also to increased accumulation of PCSK9 in plasma caused by the primary loss of LDLR.
0.96 LDLR-deficient mice had high levels of murine PCSK9 and that expression of the human PCSK9 transgene increases murine PCSK9 in wild type mice to the levels seen in LDLR-deficient mice.
0.94 LDLR having a greater effect on PCSK9 than on LDL, and human LDLR showing the opposite.
0.80 PCSK9 on LDLR and cholesterol metabolism in mice is similar to that observed in humans, and they have validated the use of the mouse to study the physiology of PCSK9.
28600283 0.98 PCSK9 might protect mice from LPS-induced death is through the reduced degradation of the LDLR and thus enhancing LPS clearance.
0.95 PCSK9 have been developed that block its interaction with the LDLR and reduce plasma LDL cholesterol levels.
0.92 PCSK9 with the LDLR potently reduces plasma LDL cholesterol levels and cardiovascular events.
0.88 PCSK9 degrades LDLRs; thus it is also possible that PCSK9 could alter sepsis outcomes through its potent regulation of the LDLR or through other as yet undiscovered mechanisms.
31178716 0.98 Proprotein convertase subtilisin/kexin type 9 (PCSK9), acts as one of the major regulators of cholesterol homeostasis, by mediating the degradation of hepatic low density lipoprotein receptors (LDLr) (Macchi et al.,).
0.98 LDLr expression is reduced by PCSK9 during brain development and after transient ischemic stroke (Rousselet et al.,).
0.92 LDLr demonstrated a beneficial effect via enhancement of Abeta clearance (Kim et al.,), suggesting its promising association with the risk for AD and consequently the involvement of PCSK9.
0.68 PCSK9 did not affect the expression of LDLR, VLDLR and apoEr2 in the mouse brain (Liu et al.,).
21773052 0.98 PCSK9 binds the EGF-A domain of the low-density lipoprotein receptor (LDLR) and favors the targeting of the LDLR to endosomes/lysosomes and its degradation (reviewed in).
0.97 PCSK9 (proprotein convertase subtilisin/kexin type 9) enhances LDLR degradation, resulting in low-density lipoprotein accumulation in plasma.
0.97 PCSK9 on the LDLR has emerged as a novel therapeutic target for hypercholesterolemia.
21810484 0.98 LDLR is also regulated post-translationally by the proprotein convertase PCSK9.
0.98 LDLR internalization and intracellular PCSK9 levels are decreased (LDLR and bound PCSK9 are both degraded upon internalization) in ABCA2 overexpressing N2a cells.
0.87 LDLR favors the internalization and recycling of the LDLR, whereas secreted PCSK9 and subsequent binding to the LDLR favors the internalization and degradation of the receptor.
28291840 0.98 PCSK9 resulted in a decrease in LDL receptor expression in the liver (Fig 1B) and an increase in plasma cholesterol levels in mice maintained on a regular chow diet (Fig 1C).
0.94 Proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that directs hepatic LDL receptors for degradation, it was shown that a single injection of recombinant adeno-associated virus (rAAV) encoding gain-of-function mutant forms of PCSK9, human PCSK9D374Y or mouse PCSK9D377Y (AAVmPCSK9), was sufficient to reduce LDL receptor expression, increase plasma LDL cholesterol and induce atherosclerosis in mice and hamsters.
0.80 proprotein convertase subtilisin/kexin type 9 (PCSK9)-encoding adeno-associated viral vector (AAVmPCSK9), avoiding the need for knockout mice models, such as low-density lipoprotein receptor deficient mice.
30524198 0.98 proprotein convertase subtilisin/kexin type 9 (Pcsk9) (Figure 4(b), center panel), a mediator of plasma cholesterol homeostasis and ligand for LDLR family members, are significantly upregulated in LDLR-/-; macLRP1-/- peritoneal macrophages isolated from mice fed a chow diet.
0.97 LDLR-/- and LDLR-/-; macLRP1-/- mice fed a standard chow or Western diet for two weeks revealed three genes that were differentially regulated: Fdps, Pcsk9, and Soat1 (Figure 4(b)).
0.95 Pcsk9 mRNA levels significantly decreased in LDLR-/-; macLRP1-/- peritoneal macrophages compared to those on a chow diet, while levels remained unchanged in LDLR-/- peritoneal macrophages regardless of diet.
31366894 0.98 PCSK9 binds to the LDLR directing it to lysosomal degradation.
0.96 Pcsk9 knock-out mice showed increased hepatic LDLR levels that were linked to reduced circulating LDL cholesterol.
0.91 PCSK9, LDLR remain on the cell surface and remove LDL particles from the circulation.
32035489 0.98 LDLR delivers non-HDL particles to the liver, and PCSK9 binds LDLR and leads to its degradation in the endosome.
0.96 PCSK9, which functions as a negatively modulator of LDLR.
0.92 LDLR-/- hamster study, we report for the first time that: 1) ezetimibe significantly promoted the protein expression of CYP7A1 and PPARgamma, and lowered the protein expression of PPARalpha and PPARbeta in the liver; 2) ezetimibe significantly up-regulated the protein expression of LXRbeta in the small intestine, but not NPC1L1 and ABCG5/G8; and 3) ezetimibe may not influence PCSK9 in the absent of LDLR.
24158514 0.98 proprotein convertase subtilisin/kexin type 9 (PCSK9) defined a cellular mechanism for controlling LDLR expression at the protein level.
0.90 PCSK9) in mouse primary hepatocytes were not affected by Ad-shHNRNPD infection (Figure 5C), thus confirming the specific targeting effect of the shRNA to hnRNP D. The reduction of hnRNP D by Ad-shHNRNPD transduction with a consequential increase in LDLR protein level was also observed in mouse hepatoma-derived cells (Figure 5D).
28504688 0.98 PCSK9 reduces hepatic uptake of LDL by increasing the lysosomal degradation of LDL receptors thereby generating an LDLR-/--like phenotype.
0.75 PCSK9 knocks down LDL receptor level in liver in C57 mice
29485998 0.98 PCSK9 protein, the LDLR-PCSK9 complex is directed to lysosomes for degradation, thereby leading to LDLR down-regulation.
27318830 0.97 PCSK9 AAV mice and Ldlr-/- mice over time (Supplementary Figure 3D).
0.96 Ldlr-/- mice on the HF/HC diet for 15 weeks exhibited more advanced aortic arch lesions compared to PCSK9 AAV mice with greater macrophage accumulation in the plaques that appears to have diminished as calcification progresses at the 20 week time point (Figure 4G).
0.94 PCSK9 AAV injection and the HF/HC diet for 20 weeks, which were similar to Ldlr-/- mice that consumed a HF/HC diet for 15 weeks (Supplementary Figure 3C).
0.93 PCSK9 AAV injection and the HF/HC diet for 15 and 20 weeks revealed alkaline phosphatase activity (TNAP-positive lesions) at the aortic sinus, lesser curvature and valve leaflets at the similar level to Ldlr-/- mice (Figure 3C-E).
0.92 PCSK9 AAV mice and Ldlr-/- mice that consumed a HF/HC diet for 15 weeks showed CD68-positive macrophages in the aortic sinus (Figure 4G).
0.92 mPCSK9 (D377Y) is sufficient to induce vascular calcification similar to that in Ldlr-/- and Apoe-/- mice, commonly utilized strains in atherosclerosis research.
0.91 PCSK9 AAV injection and a HF/HC diet for 15 weeks decreased LDLR protein levels in the liver compared to saline control mice (p < 0.0001) (Figure 1D), while LRP1 and VLDLR protein levels did not change.
0.87 PCSK9 AAV mice and Ldlr-/- mice, while calcium levels did not change (Supplementary Figure 3A, B).
0.86 PCSK9 AAV and the HF/HC diet for 15 and 20 weeks developed atherosclerotic lesions at the aortic sinus similar in size to Ldlr-/- mice (Figure 2A-C).
0.85 PCSK9 AAV injection and the HF/HC diet for 15 or 20 weeks caused aortic valve leaflet thickening similar to that seen in the Ldlr-/- mice (Figure 2A, E).
0.82 PCSK9 AAV mice that consumed the HF/HC diet for 20 weeks had significant smaller lesions compared to Ldlr-/- mice (Figure 2A, B, D).
0.77 PCSK9 was slower than of the same measures in Ldlr-/- mice on the same diet.
0.74 Ldlr-/- mice that consumed the HF/HC diet for 20 weeks developed more calcification (31.6 +- 4.1 %) compared to the 15 week group and the PCSK9 AAV group.
0.66 PCSK9 AAV mice that consumed the HF/HC diet for 20 weeks was similar to those in Ldlr-/- mice that consumed the HF/HC diet for 15 and 20 weeks (Figure 3F).
0.63 PCSK9 into C57BL/6NTac mice caused less lesion formation compared to Ldlr-/- mice on a high fat diet.
31921471 0.97 PCSK9 interacts directly with cytoplasmic apolipoprotein B (apoB) and prevents its degradation via the autophagosome/lysosome pathway, resulting in increased levels of very low-density lipoprotein (VLDL) and LDL production, which contributes to atherosclerosis development irrespective of the LDLR.
0.97 PCSK9 expressing Ldlr-/-Apobec1-/- (LDb) double knockout mice induce elevated levels of proinflammatory gene expression in endothelial cells compared to the LDLs obtained from PCSK9 deficient Ldlr-/-Apobec1-/-Pcsk9-/- (LTp) triple knockout mice.
0.97 PCSK9 is associated with changes in the polarization of IL-17-producing cells independent of its known effects on LDLR.
0.97 PCSK9 can directly interact with other receptors, such as the apoE receptor, LDLR-related protein 1, VLDL receptor, CD36, CD81, and epithelial Na+ channel.
0.97 LDLR and PCSK9 in apoE mice may confound the interpretation of the contribution of IL-17 in atherogenesis.
0.96 PCSK9 is best known for its effect on LDLR turnover, and its inhibition has resulted in dramatic reduction in plasma LDL cholesterol levels.
0.93 PCSK9 in the absence of LDLR.
0.92 PCSK9 modulates atherosclerosis development independent of LDLR.
0.91 PCSK9 may also affect atherosclerosis development via other non-LDLR-dependent mechanisms.
0.53 PCSK9 attenuates the development of atherosclerosis and this phenomenon may not be dependent on the well-known interactions between PCSK9 and LDLR.
29618348 0.97 Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted by the liver as an important regulator of cholesterol homeostasis, enhances the endosomal and lysosomal degradation of hepatic low-density lipoprotein (LDL) receptors (LDLR), resulting in increased circulating LDL-cholesterol (LDL-C) concentration.
0.97 PCSK9 and LDLR expression simultaneously, and it is possible that another regulator such as inducible degrader of LDLR (Idol) promotes degradation of LDLR.
0.97 LDLR regulation is complex, and suggests that in vivo these reagents may act through PCSK9-independent mechanism to affect LDLR expression.
0.96 LDLR possibly via PCSK9-independent pathways in db/db mice (Additional files 1, 2, 3, 4).
0.94 LDLR possibly via PCSK9-independent pathways in db/db mice.
0.93 PCSK9 and low-density lipoprotein receptor (LDLR) expression with a decrease in HNF1alpha in db/db mice but not in WT mice.
0.90 PCSK9 protein were not associated with an increase in hepatic LDLR protein in db/db mice, namely, liraglutide also inhibit LDLR.
0.87 PCSK9 and LDLR in ob/ob mice.
0.56 PCSK9, LDLR and HNF1alpha expressions in db/db mice and nondiabetic mice.
22355267 0.97 PCSK9 inhibition would lead to increased cellular cholesterol uptake and decreased SREBP tone, and also is in agreement with reductions of PCSK9/LDLR mRNA levels in the livers of mice treated with 1B20.
0.97 LDLR and PCSK9 mRNAs in 1B20-treated mice (Figure 3), confirming that the increase in liver LDLR protein was not due to increased LDLR mRNA expression, rather due to decreased post-transcriptional LDLR protein degradation.
0.97 LDLR and PCSK9 mRNAs in mouse livers following 1B20 treatment, we observed dose-dependent decreases in LDLR and PCSK9 mRNAs in human primary hepatocytes treated with 1B20 in the presence of simvastatin (Figure 11).
0.92 LDLR protein, and reduced hepatic PCSK9 and LDLR mRNAs.
0.92 PCSK9 and LDLR mRNAs in mice that paralleled the time course of LDL-C reductions in the multiple dosing study.
0.88 LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (>= 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody.
0.72 LDLR+/-] mice have circulating levels of PCSK9 that are similar to humans (~ 5 nM).
29576536 0.97 LDLR turnover, independent of PCSK9.
0.97 LDLR degradation, above and beyond PCSK9-mediated LDLR lysosomal degradation, with different effects on plasma lipids.
0.96 LDLR, by dint of gamma-secretase inhibition, allows rapid binding and uptake of TRLs, which may distinguish this approach from PCSK9 antagonism that preferentially increases LDLR recycling.
0.94 LDLR is differentially regulated by gamma-secretase and PCSK9, to affect uptake of TRLs and cholesterol respectively, is unclear.
0.92 PCSK9 reroutes internalized LDLR for intracellular degradation, we considered whether the PCSK9 action may be potentiated by previous or concomitant gamma-secretase-mediated LDLR cleavage.
0.90 LDLR include PCSK9 (pro-protein convertase subtilisin/kexin type 9) and Idol (inducible degrader of the LDLR), but we observed no difference of hepatic Pcsk9 or Idol expression, and PCSK9 protein levels and secretion with gamma-secretase inhibition (Figure S5F-S5K).
31110521 0.97 LDL receptor (LDLR) that is mainly regulated by proprotein convertase subtilisin/kexin 9 (PCSK9).
0.95 PCSK9 antibodies were found to inhibit the interaction between PCSK9 and LDLR.
0.86 PCSK9-LDLR interaction blockade by vaccine-induced PCSK9 antibodies
0.78 PCSK9 binding to LDLR by 46%, compared with plasma sample of control group.
0.55 PCSK9 to LDLR was reduced by 46% in the presence of plasma obtained from L-IFPTA+-vaccinated mice, as compared to control mice (Figure 2 D).
30386595 0.97 PCSK9, the PCSK9 secreted by HepG2-grafts is responsible for increased serum PCSK9 in mice, when glucose was provided and may be involved in reducing hepatic LDLR level in the host.
0.95 PCSK9 and LDLR protein level in presence and absence of HepG2-tumors.
0.95 PCSK9 and LDLR levels in mice with and without HepG2 xenograft.
0.82 PCSK9 while upregulated level of hepatic LDLR protein when compared with mice from group I. Overall, these observations would help in understanding the association between abnormal plasma lipid level and HCC in humans.
30449662 0.97 PCSK9 DMAb inhibits PCSK9, allowing for increased LDLR recycling and display on the cell surface.
0.96 PCSK9 inhibitors are emerging as a potent important new approach for reducing LDL-C by increasing its hepatic clearance via the LDLR.
0.96 PCSK9 was observed in vivo, showing elevated liver LDLR expression 5 days after treatment.
0.89 LDLR expression levels were significantly higher for PCSK9 DMAb-treated mice than control mice.
26333678 0.97 LDLR-/- mice (5.9+-0.9% in LDLR-/- LDLR-/- vs. 5.9+-0.8% in hPCSK9tg/LDLR-/- LDLR-/-; Figure 3D/E and Supplementary Figure 8), suggesting that PCSK9-mediated inflammation is LDR dependent.
0.96 PCSK9 internalization by MPM is LDLR-independent (Supplementary Figure 7).
28377633 0.97 PCSK9 inhibitors prevent the degradation of LDLR, which results in increased (V)LDL uptake from blood mainly by the liver and decreased plasma LDL- cholesterol levels.
0.97 LDLR can function as a receptor for drug-laden LDL (Figs 3-6) suggests that the increase in the LDLR-mediated (V)LDL uptake caused by PCSK9 inhibitors can also alter the behavior of lipoprotein-associated drugs in the body.
27470509 0.96 Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in lipoprotein metabolism through regulating LDL receptor homeostasis.
0.96 PCSK9 by mouse PCSK9 antisense oligonucleotides in LDL receptor -/- mice did not reduce AngII-induced AAAs, providing evidence that hypercholesterolemia, rather than increases of PCSK9 activity, contributes to augmented AAA formation in AngII-infused mice.
0.94 LDL receptor -/- mice had more than 10-fold higher plasma PCSK9 concentrations, compared to C57BL/6 mice (Figure 2A).
0.82 PCSK9D377Y.AAV had rapid increases of plasma cholesterol concentrations, but were lower compared to LDL receptor -/- mice fed same Western diet during the study (Figure 2B).
0.82 PCSK9D377Y.AAV and fed a Western diet is equivalent to that in LDL receptor -/- mice fed the same diet.
0.73 PCSK9D377Y.AAV and LDL receptor -/- mice, it is unclear whether their different plasma cholesterol concentrations would cause different effects on atherosclerosis in a long-term manner.
0.70 PCSK9 concentrations were not significantly changed in LDL receptor -/- mice, which were lower compared to C57BL/6 mice infected with PCSK9D377Y.AAV (Figure 2A).
0.69 PCSK9 gain-of-function mutation in C57BL/6 mice had comparable effects as LDL receptor -/- mice on AngII-induced AAAs
0.67 PCSK9D377Y.AAV in C57BL/6 mice had comparable effects as LDL receptor -/- mice on AngII-induced AAAs
0.62 PCSK9 concentrations by PCSK9 antisense oligonucleotides in male LDL receptor -/- mice did not influence AngII-induced AAAs.
24950000 0.96 LDLR/PCSK9 pathway manifested in mice by ANA in the absence of CETP inhibition and modestly impacted serum cholesterol metabolism.
0.95 LDLR, PCSK9 and other four SREBP target genes in all liver samples revealed that mRNA levels of SREBP2-target genes were reduced in the range of 20-40% in ANA group as compared to vehicle group (Fig. 7D), which were corroborative to the results of protein analyses.
0.95 Ldlr gene transcription appeared to exert a more dominant role in determination of the LDLR protein levels than the reduction of serum PCSK9.
0.91 LDLR protein levels in liver tissue and decreased serum PCSK9 levels in dyslipidemic mice
0.89 PCSK9 and liver LDLR/SREBP2-M protein.
0.86 PCSK9 levels, liver LDLR protein amounts were lower in ANA treated mice as compared to control mice fed the HFHC diet.
0.71 PCSK9 and LDLR gene expression.
29065174 0.96 Pcsk9 in chaperoning LDLr for degradation, the DualAG induced decline in Pcsk9 expression is in agreement with elevated LDLr expression.
0.94 LDLr was accompanied by an decline in Pcsk9 protein expression.
0.92 Pcsk9 was noted, which could explain the increase in LDLr expression.
0.73 Pcsk9, ApoB48, ApoB100, and hepatic LDLr can be attributed to Gcgr action, as activation of Glp1 alone (Liraglutide) was not able to produce these effects.
28302950 0.95 LDLR demonstrated that PCSK9 did not affect the expression of genes and proteins involved in hepatic lipogenesis (both SREBP- and non-SREBP-mediated), findings that differ from what was seen in the intestine).
0.89 LDLR knockout (KO) mice, which have a 15-fold increase in plasma LDL-C, this PCSK9 overexpression model exhibits a more modest (5-fold) increase in plasma LDL-C despite the fact that, as in the LDLR KO model, there is no demonstrable LDLR in the liver).
0.86 PCSK9-induced plaque inflammation, independent of plasma lipid changes, comes from studies of apoE-/- and LDLR-/- mice expressing hPCSK9 from bone marrow-derived cells).
0.77 PCSK9 in LDLR-/- mice has little to no effect on plasma lipids and atherosclerosis).
30646909 0.94 PCSK9 normally binds to a LDL receptor with subsequent internalization of both molecules.
0.93 LDLR gene(s) have higher levels of circulating PCSK9 protein.
0.88 LDL receptor availability, there might then be an additional reduction in PCSK9 plasma levels.
30354208 0.94 Ldlr mRNA levels significantly to 1.7-fold of control, whereas other typical SREBP2-target genes such as Pcsk9 and Hmgcr were unaffected by OCA.
0.90 Ldlr transcription nor inhibit PCSK9-mediated degradation of LDLR protein in the liver of normolipidemic mice.
26965651 0.94 LDLR is directed to the lysosome for proteolysis:which is induced by either PCSK9 (refs) or IDOL:or retrieved and recycled back to the cell surface.
29183623 0.94 PCSK9 silencing, by increasing LDLR activity, would enhance the Angptl3 siRNA effect on LDL-C levels.
27981884 0.93 PCSK9 binding to LDL-receptor, but since it allows cleavage of the protein, FL PCSK9 levels do not accumulate in the serum of the animals.



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