Publication for Hmgcs2 and Ppara

Species	Symbol	Function*	Entrez Gene ID*	Other ID	Gene coexpression	CoexViewer
mmu	Hmgcs2	3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2	15360			[link]
mmu	Ppara	peroxisome proliferator activated receptor alpha	19013

Pubmed ID	Priority	Text
30048968	0.99	HMGCS2 and PDK4 genes are transcriptionally regulated by PPAR-gamma via PPAR responsive element (PPRE) and PPAR-gamma coactivator 1 (PGC-1).
20011657	0.98	mHMG-CoA synthase in pituitary gland of wild-type mice indicating PPARalpha activation.
	0.97	PPARalpha target genes analysed in brain, mHMG-CoA synthase was upregulated strongest by fasting.
	0.97	mHMG-CoA synthase and LCAD were the only PPARalpha responsive genes that were considerably upregulated by clofibrate treatment in brain, with the strongest effects in frontal cortex followed by pituitary gland and diencephalon.
	0.97	PPARalpha mediated upregulation of mHMG-CoA synthase in brain of PPARalpha knockout mice upon fasting.
	0.96	mHMG-CoA synthase in livers of wild-type mice upon fasting could not be observed in the livers of PPARalpha knockout mice indicating the PPARalpha-dependent regulation of mHMG-CoA synthase in liver.
	0.94	PPARalpha knockout mice mRNA concentration of mHMG-CoA synthase was increased upon fasting but not as strong as in wild-type mice.
	0.88	mHMG-CoA synthase was increased upon fasting in wild-type mice but not in PPARalpha knockout mice and was lower in PPARalpha knockout mice than in wild-type mice (P < .05; see Figure 3).
	0.84	mHMG-CoA synthase mRNA in PPARalpha knockout mice but this effect was less than that observed in wild-type mice (P < .05; Figure 3).
26869992	0.98	PPARa is directly responsible for driving the transcription of HMGCS2 during fasting or in response to a ketogenic diet (KD).
	0.98	HMGCS2 involved in steroid synthesis, is neither transcriptionally regulated by PPARa nor does it physically interact with this receptor.
	0.97	HMGCS2 expression is unique, as it involves the binding of the HMGCS2 protein itself to the PPARa receptor.
	0.97	HMGCS2 and PGC-1a factor responsible for the mitochondrial biogenesis (A) in the cells treated with fenofibrate (FF) and the PPARa inhibitor (MK886) in the B16 F10 cells expressing normal (Ctrl shRNA) or reduced (PPARa shRNA) levels.
	0.96	PPARa does not play a role as an HMGCS2 transactivator or that the process might also be regulated downstream of transcription - perhaps through altered protein stability or turnover rate.
	0.95	HMGCS2 expression (B), which precedes a significant increase in the beta-hydroxybutyrate (bHB) production (C), independently of the PPARa level.
	0.94	PPARa shRNA generating cells (Figure 3C), which suggests that although HMGCS2 expression can be triggered quite rapidly, metabolic adaptation to the fenofibrate challenge takes nearly 2 days.
	0.91	HMGCS2 level was even higher in the B16 F10 cells with reduced PPARa expression (Figure 3A).
25390336	0.98	PPARalpha KO mice is further demonstrated by the low HMGCS2 mRNA abundance in the liver of fasting PPARalpha KO mice compared to a strong induction in WT mice upon fasting.
	0.98	HMGCS2 mRNA level was completely different with higher levels in the fed state and stronger fasting-induced increase of HMGCS2 mRNA in PPARalpha KO compared to WT mice.
	0.97	HMGCS2 were lower in PPARalpha KO mice than in corresponding WT mice (Figure 2).
	0.97	HMGCS2 was also induced upon fasting in these tissues of PPARalpha KO mice; in liver, kidney, heart and pituitary gland this increase was less pronounced than in fasted WT mice (Figure 2).
	0.96	HMGCS2 mRNA concentration was higher in PPARalpha KO than in WT mice.
	0.86	PPARalpha activation, we analyzed the relative mRNA concentration of a typical PPARalpha target gene, namely 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS)-2, in liver, kidney, heart, small intestine, hypothalamus, pituitary gland and thyroid gland of the mice.
	0.57	3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS)-2 in mouse tissues in response to fasting and PPARalpha.
25904331	0.98	Peroxisome proliferator-activated receptor alpha, a transcriptional activator of HMGCS2, is similarly down-regulated.
	0.98	HMGCS2 is regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), which also regulates many changes in fatty acid and glucose metabolism by heterodimerizing with retinoid X receptor and binding to peroxisome proliferator hormone response elements on DNA of target genes.
	0.98	PPARalpha, which has been shown to have a stimulatory effect on hepatic HMGCS2 expression.
	0.97	HMGCS2, we find that 4) the HMGCS2 transcriptional regulator PPARalpha and the SCFA (butyrate) transporter MCT1 are down-regulated in the K8-/- colon, whereas 5) luminal butyrate levels are increased 6) without changes in the composition of the butyrate-producing bacteria.
	0.96	HMGCS2 and PPARalpha are decreased and HMGCS2 is mislocalized in adult colon but not in small intestine or liver of K8-/- mice.
	0.96	PPARalpha under baseline and ketogenic conditions in K8-/- mice, in line with the expression of HMGCS2 (Figures 2 and 4).
27982131	0.98	PPARalpha in the liver, including those encoding acyl-CoA oxidase (Acox1), which is involved in the peroxisomal beta-oxidation of fatty acids; Cpt1a, which transports fatty acids across the outer mitochondrial membrane; and HMGCS2.
	0.98	HMGCS2 to deacetylate it, was downregulated in KD-fed Creb3l3-/- and Ppara-/- mice and further downregulated in Creb3l3-/-Ppara-/- mice (Fig. 2b).
	0.98	PPARalpha target genes Acox1, Hmgcs2, Hmgcl, and Bdh1 were significantly downregulated in the liver of Ppara-/- mice compared with WT mice (Fig. 5b).
	0.97	Hmgcs2 was blunted in Ppara-/- and Creb3l3-/-Ppara-/- mice and not in Creb3l3-/-mice, indicating that PPARalpha governs Hmgcs2 expression.
	0.96	Hmgcs2, which encode the rate-limiting enzymes for fatty acid oxidation and ketogenesis, were blunted in KD-fed Ppara-/- and Creb3l3-/-Ppara-/- mice.
	0.95	Ppara and Cpt1a, and the ketogenesis genes Hmgcs2, Bdh1, Fgf21, and Creb3l3 were also significantly upregulated in KD-fed WT mice compared with that in MF-fed WT mice (Fig. 7c) but significantly downregulated in KD-fed Creb3l3-/- mice compared with that in KD-fed WT mice.
29482168	0.98	Ppara, Acadl, Acox1, Cpt1a and Hmgcs2 (Fig. 4E).
	0.98	Ppara, Acadl, Acox1, Cpt1a and Hmgcs2 (Fig. 5E).
	0.98	Ppara, Pgc1a, Cpt1a, Acox and Hmgcs2 (Fig. 6O).
	0.98	Ppara, Pgc1a Cpt1a, Acox1 and Hmgcs2) in the livers of fasted mice (Fig. 3), as well as the mice with STZ-induced type 1 diabetes (Fig. 4).
	0.96	Ppara, Peroxisome proliferator-activated receptor gamma coactivator 1alpha (Pgc1a), Acyl-Coenzyme A dehydrogenase (Acadl), Acyl-Coenzyme A oxidase 1 (Acox1), Carnitine palmitoyltransferase 1a (Cpt1a) and 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (Hmgcs2) (Fig. 3G), but showed no impacts on expression levels of other genes involved in liver metabolism, such as lipogenesis, fatty acid uptake and vLDL secretion (Fig. 3H).
24944901	0.98	PPARalpha-regulated genes were down regulated and both Pdk4 and Hmgcs2 were upregulated in liver tissue from LDKO mice compared to controls (Figure 3A).
	0.97	PPARalpha-mediated gene transcription since only CPT1a was decreased in LKDO liver tissue compared to flox controls, while five other PPARalpha regulated genes were unaltered or upregulated (Pdk4 and Hmgcs2).
	0.92	PPARalpha-regulated genes: Pdk4, Fgf21, Acox1, Hmgcs2 and Ppara.
30181250	0.98	PPAR-regulated gene expression was not inhibited in enterocytes cocultured with L. paracasei, and PPAR targets fatty acid binding protein 2 (Fabp2), which prevents FA transport back to the lumen, and 3-hydroxy-3-methylglutaryl-CoA (HMGC) synthase 2 (Hmgcs2), involved in ketogenesis, showed ~8-fold overexpression (Fig. 3B).
	0.98	PPAR targets involved in TG and lipoprotein biosynthesis and ~30-fold overexpression of Fabp2 and Hmgcs2 (Fig. 2B).
	0.96	PPAR targets involved in beta-oxidation (Hmgcs2, Cpt1a) and TG biosynthesis (Dgat2) was downregulated compared to control mice on a HFD (Fig. 7J and K), suggesting decreased FA intracellular levels; this, along with the results of LD fluorescence imaging, which did not show modifications of intracellular LD in comparison to CD, supports the idea of decreased dietary fat absorption by enterocytes in L. paracasei mice.
30621686	0.98	PPARalpha, acyl-CoA oxidase 1 (Acox1), carnitine palmitoyltransferase 1 (Cpt1), and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) in liver of db/db mice, was significantly increased by crocin (Fig. 3f-i).
	0.98	PPARalpha, Acox1, Cpt1 and Hmgcs2.
	0.97	PPARalpha, acyl-CoA oxidase 1, carnitine palmitoyltransferase 1, and 3-hydroxy-3-methylglutaryl-CoA synthase 2.
30879920	0.98	Pparalpha, Cpt1a, Acox1, Pgc1alpha, Hmgcs2, etc.) and secretion (Mttp) were significantly reduced in the Arid1aLKO mice with HFD administration.
	0.98	Pparalpha, Acox1, Cpt1alpha, and Hmgcs2, in the primary mouse hepatocytes (Fig. 6a) and immortalized hepatocytes with SV40 expression (Supplementary Fig. 6).
	0.98	PPARalpha, but not PPARgamma partially recovered the defective expression of its downstream target genes Acox1, Cpt1a, and Hmgcs2 in Arid1a-/- hepatocytes (Fig. 6e and Supplementary information, Fig. 8).
30952952	0.98	PPARalpha in livers of control mice was evidenced by a induction of transcript levels of its bona fide targets in fatty acid transport to mitochondria, ketogenesis and fatty acid oxidation, Cpt2, Hmgcs2 and Aox, respectively (Fig. 2e).
	0.98	PPARalpha target genes in FAO (Aox) and ketogenesis (Hmgcs2) (Fig. 3g).
	0.98	PPARalpha target genes involved in FAO (Aox), ketogenesis (Hmgcs2) and peroxisome function (Pex6) (Fig. 7e, f).
22988513	0.98	3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), which is a Ppara target.
	0.93	Ppara target such Cpt1a did not differ due to CLA but the expression of the ketogenic regulator Hmgcs2 (CLA = 0.13 versus control = -0.16 and enzyme Bdh1 (CLA = 0.13 versus control = -0.20) was upregulated with CLA.
23497718	0.98	PPARalpha target genes involved in fatty acid uptake (FABP4, SLC25A20), fatty acid oxidation (ACOX1, CYP4A24) and ketogenesis (HMGCS2, FGF21) (P < 0.05, Table 2).
	0.96	PPARalpha target genes involved in fatty acid uptake (FABP4, SLC25A20), fatty acid oxidation (ACOX1, CYP4A24) and ketogenesis (HMGCS2, FGF21) were elevated in the liver of lactating compared to non-lactating sows (P < 0.05).
23957789	0.98	HMGCS2, a key gene involved in ketogenesis, is regulated by PPARalpha.
	0.96	PPARalpha knockout and torpor, and were enriched in mitochondrial fatty acid beta oxidation (HADHB, ACADL, and ACADVL) and PPAR signaling (EHHADH, ACADL, ACOX1, HMGCS2, and SLC27A2).
24858472	0.98	PPAR)-alpha mechanism, namely Hmgcs2 and Pdk4 ; whereas the mRNA level of Oxct1, which is not clearly regulated by PPAR-alpha, is differently affected by FATP1.
	0.98	PPAR-alpha target genes Hmgcs2 and Pdk4.
26541158	0.98	PPARalpha activation leads to stimulation of ketogenesis, and both Hmgcs2 and Cpt1a are downstream genes of PPARalpha.
	0.97	PPARalpha and Hmgcs2) and decreased ketolytic enzyme gene expression (succinyl-CoA-3-oxoacid CoA transferase, Scot, and acetoacetyl-CoA synthetase, Aacs) in the hypothalamus and cortex.
27439777	0.98	PPARalpha is the master regulator of fatty acid beta-oxidation and ketogenesis, while SIRT3 deacetylates and activates mitochondrial HMGCS2, promoting ketogenesis in the fasted state.
	0.78	peroxisome proliferator-activated receptor alpha (PPARalpha), sirtuin 3 (SIRT3), 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2), and 3-hydroxybutyrate dehydrogenase, type 1 (BDH1) in mitochondria from these mice (Fig. 5A).
27669233	0.98	Hmgcs2, was decreased in Pparalpha-/- mice compared to wild-type mice.
	0.98	Hmgcs2, Fgf21, and Acat1, were increased upon starvation regardless of the diet in a PPARalpha-dependent manner (Figure 4c,d, Figure S1d).
27708682	0.98	PPARalpha, a NEFA activated nuclear hormone receptor, which promotes expression of genes essential to enhanced ketogenesis (CPTI, HMGCS2, BDH1, and UCP2).
	0.94	PPARalpha, CPTI, HMGCS2, BDH1, and BDH2 mRNA expression changes in response to refeeding.
29422939	0.98	PPAR-response gene, Hmgcs2, the mitochondrial enzyme in ketone body production, was significantly increased in liver by all three interventions (Fig. 2h).
	0.98	PPARalpha-genes Cd36 and Hmgcs2, involved in fatty acid import and keton body production, respectively.
30926862	0.98	Hmgcs2, a mitochondrial enzyme involved in the ketogenesis pathway and regulated in part by PPARA, was decreased at both mRNA and protein levels (Fig. 7B,C).
	0.98	PPARalpha-regulated mitochondrial Hmgcs2, the rate-limiting enzyme involved in the production of ketone bodies, including beta-hydroxybutyrate, a known endogenous HDAC inhibitor, is decreased in mutant enteroids.
17925015	0.98	Pparalpha itself and a number of PPARalpha-dependent genes involved in fatty-acid beta-oxidation (e.g. Acadvl, Dci) and ketone-body synthesis (e.g. Hmgcs2) were induced in the intestine upon fasting.
20154695	0.98	PPAR target genes, including Acaa1b, Angptl4, Mgll and Hmgcs2 , in Cftr-/- cells and restoration of their expression by Ro treatment (Fig. 2a and Supplementary Fig. 2a).
22441164	0.98	PPARalpha target genes was significantly decreased in 129 Pex2-/- versus control mouse liver, including carnitine palmitoyltransferase 1a (CPT-1a), which has a pivotal role in the regulation of mitochondrial beta-oxidation, CYP4A10, a microsomal omega-oxidation enzyme, and mitochondrial HMG-CoA synthase (HMGCS2), which is a key control site of ketogenesis.
23894377	0.98	PPARalpha was significantly decreased three fold in both BAT and liver of cold stressed mice in association with decreased expression of a number of genes regulating cholesterol and fatty acid transport and metabolism which have been proposed to be regulated by PPARalpha, including Apoa1, Apoa2, Apoc3, Hmgcs2, Cyp7a1.
24191950	0.98	Ppara target genes (Pck1, G6pc, Pcx, Gyk, Hmgcs2, Fgf21; see and references therein) arguing for the central role of this transcription factor during fasting, evident from the phenotype of fasted Ppara knock-out mice.
24265809	0.98	PPARalpha agonist GW7647, CFE treatment significantly induced expression of genes responsible for fatty acid beta-oxidation such as the acyl-CoA oxidase 2 (ACOX2), the carnitine palmitoyltransferase 2 (CPT 2) and the enoyl CoA hydratase 1 (ECH1), and of the ketogenic HMG-CoA synthase 2 (HMGCS2) gene (Figure 2C).
24773203	0.98	PPARalpha also regulates genes in other metabolic pathways such as Hmgcr, Hmgcs2, and Scd, and some PPARalpha downstream genes were reported to be induced, while others were down-regulated.
25383754	0.98	Hmgcs2 has been shown to interact with PPARalpha and acts as a co-activator to up-regulate transcription of genes of lipid metabolism.
26977393	0.98	Hmgcs2 (by more than 7-fold) which are both regulated by activation of PPARalpha.
28129657	0.98	PPARalpha (ACOX1 and CPT1), PPARbeta/delta (PDK4 and HMGCS2), and PPARgamma (SCD1 and ACC) were significantly elevated by the MHY2013 treatment (Figure 2I).
28249286	0.98	HMGCS2, both transcriptionally regulated by PPARalpha, were increased in FGF21 transgenic mice suggesting a posttranslational effect by which FGF21 regulates ketogenesis.
28826372	0.98	HMGCS2 gene expression is also regulated indirectly by the target of rapamycin complex mTORC1; mTORC1 inhibition is required for the activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and fibroblast growth factor 21 (FGF21), both of which are required to induce ketogenesis.
29523524	0.98	HMGCS2 also indirectly interacts with PPAR-alpha, wherein fatty acids can induce expression of HMGCS2 in a PPAR-alpha dependent manner, and, moreover, HMGCS2 can self-regulate its own transcription by directly interacting with PPAR-alpha upon translocation to the nucleus.44 This is an important interaction given that studies have shown that PPAR-alpha activation improves insulin resistance and prevents the development of diabetes mellitus.45 Studies in mice have shown that absence of HMGCS2 impairs the process of ketogenesis because of insufficient derivation of ketone bodies from fatty acids.
31916705	0.98	PPARalpha decline, some PPARalpha-responsive genes such as Hmgcs2 follow the gradual decline in mRNA levels in liver after sepsis (Fig 2E).
23741310	0.97	Pparalpha and 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (HMGCS2, encoded by Hmgcs2) mRNAs in the liver (Figure 5B).
	0.97	Hmgcs2 is a target gene of PPARalpha and a key enzyme in ketogenesis, we consider that the fetuses of DR mice were under fasting conditions that produced ketogenic responses not only in the liver but also in the brain.
	0.97	Pparalpha and Hmgcs2, a main target gene of PPARalpha, was increased in the fetal DR mice, indicating that they were under a fasting condition.
27301791	0.97	PPARalpha target genes, such as Acox1, Cpt2, Hmgcs2, Hadh, Acadm, and Acadl were similar between WT and Creb3l3-/- livers, except Cpt1a which appeared to be regulated by both CREBH and PPARalpha (Fig. 2C).
	0.97	PPARalpha and its target genes, Acox1, Hmgcs2 and Cpt1a in Creb3l3-/- mice (Supplementary Fig. 4B,C), which might have helped to improve the hepatic steatosis.
29363671	0.97	PPAR subtypes), rosiglitazone (which selectively activates PPAR gamma), or WY-14643 (which activates PPAR alpha, gamma and delta) completely reversed the impaired glucose tolerance in TLR4DeltaIEC mice (Figure 5C), and restored the expression of these PPAR-regulated genes, namely Fiaf, Fatp1, Hmgcs2, and Fabp1 (Figure 5D).
	0.95	PPAR-regulated genes that were down-regulated included fasting induced adipose factor (Fiaf), fatty acid transport protein 1 (Fatp1), 3-hydroxy-3methylglutaryl-CoA synthase 2 (Hmgcs2) and fatty acid-binding protein 1 (Fabp1) (Figure 5A).
24834104	0.97	Hmgcs2 (mitochondrial rate limiting enzyme in ketone body formation) was upregulated in the FO group but not appreciably by KO (Figure 2, see "Additional metabolic pathways" and "Mitochondrial pathways"), suggesting a more potent PPARalpha-activation by FO.
31668396	0.97	PPARalpha and HMGCS2 are also known to increase the expression of the hepatokine FGF21, and we noted a major increase in the expression of FGF21 in the livers of the PAR2-KO mice.
26909306	0.96	Hmgcs2 and to a lesser extent Pparalpha displayed reduced mRNA levels upon CA treatment, when compared to vehicle-treated cells.
31374856	0.96	PPARalpha interaction probably inhibited the expression of the acetyl-Coenzyme A acyltransferase 1B (Acaa1b), of the acyl-coA thioesterase 3 (Acot3), of Krt23 and Rab30, of the rate-limiting enzyme in ketogenesis 3-hydroxy-3-methylglutaryl-CoenzymeA synthase 2 (Hmgcs2) and of the hepatokine Fgf21, all of which are well-described PPARalpha targets.
29879903	0.95	PPARalpha targets connected to lipid metabolism, including FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2.
	0.89	PPARalpha targets such as FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2.
27829137	0.94	Ppara, Acadm, and Hmgcs2 and lowered fasting glucose and ketone levels while elevating fasting corticosterone levels (Figures 3D-3F).
	0.94	Ppara, Acadm, and Hmgcs2, but also the ketogenic response to the octanoate challenge (Figures 4A and 4B).
19154582	0.93	PPARalpha deficient mice and wild-type mice on PC2 is explained by PPARalpha target genes (Peci, Cyp4a10, Cyp4a14, Acox1, Acaa1b, Hmgcs2, Cpt2) or genes involved in hepatic detoxification (Cyp3a11).
	0.72	PPARalpha target genes (Peci, Cyp4a10, Cyp4a14, Acox1, Acaa1b, Hmgcs2, Cpt2) or genes involved in hepatic detoxification (Cyp3a11).
22338096	0.81	PPAR-alpha target genes that are involved in ketogenesis and fatty acid oxidation, such as HMGCS2, CPT1a, very long-chain acyl-CoA dehydrogenase (ACADVL), acyl-CoA synthase long-chain family member 1 (ACSL1), acyl-CoA oxidase (ACO), and liver fatty acid-binding protein (L-FABP).