Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR.
Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) has been shown to regulate adaptive thermogenesis and glucose metabolism. Here we show that PGC-1alpha regulates triglyceride metabolism through both farnesoid X receptor (FXR)-dependent and -independent pathways. PGC-1alpha increases FXR activity through two pathways: (1) it increases FXR mRNA levels by coactivation of PPARgamma and HNF4alpha to enhance FXR gene transcription; and (2) it interacts with the DNA-binding domain of FXR to enhance the transcription of FXR target genes. Ectopic expression of PGC-1alpha in murine primary hepatocytes reduces triglyceride secretion by a process that is dependent on the presence of FXR. Consistent with these in vitro studies, we demonstrate that fasting induces hepatic expression of PGC-1alpha and FXR and results in decreased plasma triglyceride levels in wild-type but not in FXR-null mice. Our data suggest that PGC-1alpha plays an important physiological role in maintaining energy homeostasis during fasting by decreasing triglyceride production/secretion while it increases fatty acid beta-oxidation to meet energy needs.
Zhang
Yanqiao
Y
Department of Biological Chemistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Castellani
Lawrence W
LW
Sinal
Christopher J
CJ
Gonzalez
Frank J
FJ
Edwards
Peter A
PA
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051557:Hepatocyte Nuclear Factor 4; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000242:Cyclic AMP; D004247:DNA; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C496593:Hnf4a protein, mouse; C501970:Tcfl4 protein, mouse; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1