CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ

Stephan Herzig, Susan Hedrick, Ianessa Morantte, Seung Hoi Koo, Francesco Galimi, Marc Montminy

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215 Citations (Scopus)

Abstract

Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-γ, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-γ expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-γ by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

Original languageEnglish
Pages (from-to)190-193
Number of pages4
JournalNature
Volume426
Issue number6963
DOIs
Publication statusPublished - 2003 Nov 13

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    Herzig, S., Hedrick, S., Morantte, I., Koo, S. H., Galimi, F., & Montminy, M. (2003). CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. Nature, 426(6963), 190-193. https://doi.org/10.1038/nature02110