Unknown

Dataset Information

0

PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis.


ABSTRACT: 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.

SUBMITTER: Estall JL 

PROVIDER: S-EPMC2799738 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis.

Estall Jennifer L JL   Ruas Jorge L JL   Choi Cheol Soo CS   Laznik Dina D   Badman Michael M   Maratos-Flier Eleftheria E   Shulman Gerald I GI   Spiegelman Bruce M BM  

Proceedings of the National Academy of Sciences of the United States of America 20091214 52


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,  ...[more]

Similar Datasets

| S-EPMC4865931 | biostudies-literature
| S-EPMC8085086 | biostudies-literature
| S-EPMC6217750 | biostudies-literature
| S-EPMC3367514 | biostudies-literature
| S-EPMC7840129 | biostudies-literature
| S-EPMC6999712 | biostudies-literature
| S-EPMC7917273 | biostudies-literature
| S-EPMC3039370 | biostudies-literature
2016-07-20 | GSE79166 | GEO
2016-07-20 | E-GEOD-79166 | biostudies-arrayexpress