Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR
- Yanqiao Zhang1,2,
- Lawrence W. Castellani2,
- Christopher J. Sinal4,
- Frank J. Gonzalez5, and
- Peter A. Edwards1,2,3,6
- 1Department of Biological Chemistry, 2Department of Medicine, and 3Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA; 4Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada; 5Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA
Abstract
Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) has been shown to regulate adaptive thermogenesis and glucose metabolism. Here we show that PGC-1α regulates triglyceride metabolism through both farnesoid X receptor (FXR)-dependent and -independent pathways. PGC-1α increases FXR activity through two pathways: (1) it increases FXR mRNA levels by coactivation of PPARγ and HNF4α 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-1α 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-1α and FXR and results in decreased plasma triglyceride levels in wild-type but not in FXR-null mice. Our data suggest that PGC-1α plays an important physiological role in maintaining energy homeostasis during fasting by decreasing triglyceride production/secretion while it increases fatty acid β-oxidation to meet energy needs.
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Footnotes
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Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1138104.
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↵6 Corresponding author. E-MAIL pedwards{at}mednet.ucla.edu; FAX (310) 794-7345.
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- Accepted December 1, 2003.
- Received July 30, 2003.
- Cold Spring Harbor Laboratory Press