MAFG is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism

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

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish
Pages (from-to)298-311
Number of pages14
JournalCell Metabolism
Volume21
Issue number2
DOIs
Publication statusPublished - 2015 Feb 3

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    De Aguiar Vallim, T. Q., Tarling, E. J., Ahn, H., Hagey, L. R., Romanoski, C. E., Lee, R. G., Graham, M. J., Motohashi, H., Yamamoto, M., & Edwards, P. A. (2015). MAFG is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism. Cell Metabolism, 21(2), 298-311. https://doi.org/10.1016/j.cmet.2015.01.007