ArticleThe Journal of biological chemistry2011
Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86 citing papers in PubMed, 140 citations in OpenAlex.
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- Microbiota-derived IPA protects against colitis by regulating intestinal HMGCS2-mediated ketogenesis to facilitate mucosal healing.Nature communications · 2026Article
- Single cell and spatial transcriptomic profiling of the type 2 diabetic coronary microcirculation and myocardium.Basic research in cardiology · 2025Article
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- Muscle transcriptome profiles in elite male ultra-endurance athletes acclimated to a high-carbohydrate versus low-carbohydrate diet.Scientific reports · 2025Article
- Targeting mitochondrial metabolism by the mitotoxin bromoxib in leukemia and lymphoma cells.Cell communication and signaling : CCS · 2024Article
- Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder.Acta pharmacologica Sinica · 2024Article
- BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.Cancer letters · 2024Article
- Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology.Communications medicine · 2024Article
- Relationship between serum β-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD.American journal of physiology. Endocrinology and metabolism · 2024Article
- METTL16 inhibits papillary thyroid cancer tumorigenicity through mCellular and molecular life sciences : CMLS · 2024Article
- Ketones and the cardiovascular system.Nature cardiovascular research · 2023Review
- Intestinal Carnitine Status and Fatty Acid Oxidation in Response to Clofibrate and Medium-Chain Triglyceride Supplementation in Newborn Pigs.International journal of molecular sciences · 2023Article
- More than a Feeling: Dermatological Changes Impacted by Spaceflight.Research square · 2023Article
- Prioritizing Pesticides of Potential Concern and Identifying Potential Mixture Effects in Great Lakes Tributaries Using Passive Samplers.Environmental toxicology and chemistry · 2023Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
HMGCS2 (hydroxymethylglutaryl CoA synthase 2), the gene that regulates ketone body production, is barely expressed in cultured cell lines. In this study, we restored HMGCS2 expression and activity in HepG2 cells, thus showing that the wild type enzyme can induce fatty acid β-oxidation (FAO) and ketogenesis, whereas a catalytically inactive mutant C166A did not generate either process. Peroxisome proliferator-activated receptor (PPAR) α expression also induces fatty acid β-oxidation and endogenous HMGCS2 expression. Interestingly, PPARα-mediated induction was abolished when HMGCS2 expression was down-regulated by RNAi. These results indicate that HMGCS2 expression is both sufficient and necessary to the control of fatty acid oxidation in these cells. Next, we examined the expression pattern of several PPARα target genes in this now "ketogenic" HepG2 cell line. FGF21 (fibroblast growth factor 21) expression was specifically induced by HMGCS2 activity or by the inclusion of the oxidized form of ketone bodies (acetoacetate) in the culture medium. This effect was blunted by SirT1 (sirtuin 1) RNAi, so we propose a SirT1-dependent mechanism for FGF21 induction by acetoacetate. These data suggest a novel feed-forward mechanism by which HMGCS2 could regulate adaptive metabolic responses during fasting. This mechanism could be physiologically relevant, because fasting-mediated induction of liver FGF21 was dependent on SirT1 activity in vivo.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.