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PGC-1α negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erbα axis

2009; National Academy of Sciences; Volume: 106; Issue: 52 Linguagem: Inglês

10.1073/pnas.0912533106

1091-6490

Jennifer L. Estall, Jorge L. Ruas, Cheol Soo Choi, Dina Laznik, Michael K. Badman, Eleftheria Maratos–Flier, Gerald I. Shulman, Bruce M. Spiegelman,

Epigenetics and DNA Methylation

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-1alpha, 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-1alpha. Importantly, PGC-1alpha-mediated reduction of FGF21 expression is dependent on Rev-Erbalpha and the expression of ALAS-1. ALAS-1 is a PGC-1alpha target gene and the rate-limiting enzyme in the synthesis of heme, a ligand for Rev-Erbalpha. Modulation of intracellular heme levels mimics the effect of PGC-1alpha on FGF21 expression, and inhibition of heme biosynthesis completely abrogates the down-regulation of FGF21 in response to PGC-1alpha. Thus, PGC-1alpha can impact hepatic and systemic metabolism by regulating the levels of a nuclear receptor ligand.