期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 52, 页码 22510-22515出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0912533106
关键词
liver; metabolism; diabetes; coactivator; fasting
资金
- H. L. Holmes Award (National Research Council of Canada)
- Canadian Institutes of Health Research
- National Institutes of Health [R01 DK-061562, R01 DK-40936, P30 DK-45735, U24 DK-59635]
FGF21 is a hormone produced in liver and fat that dramatically improves peripheral insulin sensitivity and lipid metabolism. We show here that obese mice with genetically reduced levels of a key hepatic transcriptional coactivator, PGC-1 alpha, have improved whole-body insulin sensitivity with increased levels of hepatic and circulating FGF21. Gain-and loss-of-function studies in primary mouse hepatocytes show that hepatic FGF21 levels are regulated by the expression of PGC-1 alpha. Importantly, PGC-1 alpha-mediated reduction of FGF21 expression is dependent on Rev-Erb alpha and the expression of ALAS-1. ALAS-1 is a PGC-1 alpha target gene and the rate-limiting enzyme in the synthesis of heme, a ligand for Rev-Erb alpha. Modulation of intracellular heme levels mimics the effect of PGC-1 alpha on FGF21 expression, and inhibition of heme biosynthesis completely abrogates the down-regulation of FGF21 in response to PGC-1 alpha. Thus, PGC-1 alpha can impact hepatic and systemic metabolism by regulating the levels of a nuclear receptor ligand.
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