title: Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Vilà-Brau
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: De Sousa-Coelho
authors.forename: Cristina
authors.initials: C
authors.lastname: Mayordomo
authors.forename: Diego
authors.initials: D
authors.lastname: Haro
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Marrero
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D005215:Fasting / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics / Q000378:metabolism*; D007657:Ketone Bodies / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007657:Ketone Bodies; D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D006904:Hydroxymethylglutaryl-CoA Synthase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1