MAFG is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2015 Feb 5

PMID 25651182

Citations 47

Authors

Thomas Q de Aguiar Vallim

Elizabeth J Tarling

Hannah Ahn

Lee R Hagey

Casey E Romanoski

Richard G Lee

Mark J Graham

Hozumi Motohashi

Masayuki Yamamoto

Peter A Edwards

Affiliations

Soon will be listed here.

Abstract

Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.

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