Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 23, Pages 20423-20430Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.235044
Keywords
-
Categories
Funding
- Spanish Ministerio de Educacion y Ciencia [BFU2007-67322/BMC, SAF2010-15217]
- Catalan government (Ajut de Suport als Grups de Recerca de Catalunya) [2005SGR00857, 2009SGR163]
- Catalan government
- Fundacao para a Ciencia e a Tecnologia through the Portuguese government
- [RCMNC03/08]
Ask authors/readers for more resources
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 beta-oxidation (FAO) and ketogenesis, whereas a catalytically inactive mutant C166A did not generate either process. Peroxisome proliferator-activated receptor (PPAR) alpha expression also induces fatty acid beta-oxidation and endogenous HMGCS2 expression. Interestingly, PPAR alpha-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 PPAR alpha 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available