Journal
CELL METABOLISM
Volume 21, Issue 2, Pages 298-310Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.01.007
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Funding
- United States Public Health Service [1R01DK102559-01]
- Laubish fund at UCLA
- American Heart Association (AHA) [13BGIA17080038]
- NIH [K99HL118161]
- AHA Postdoctoral Fellowship [12POST11760017]
- NIH NHLBI [K99HL12348501]
- AHA Scientist Development Grant [14SDG18440015]
- University of California Los Angeles (UCLA) Clinical and Translational Science Institute (CTSI) grant [UL1TR000124]
- UCLA Center for Ulcer Research and Education (CURE): Digestive Diseases Research Center (DDRC) [DK41301]
- UCLA Diabetes Research Center (DRC) [DK063491]
- Grants-in-Aid for Scientific Research [26111002, 26670150] Funding Source: KAKEN
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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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