title: MAFG is a transcriptional repressor of bile acid synthesis and metabolism.
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.
authors: Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: tvallim@mednet.ucla.edu.
authors: Thomas Q
authors: TQ
authors: de Aguiar Vallim
authors: Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors: Elizabeth J
authors: EJ
authors: Tarling
authors: Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors: Hannah
authors: H
authors: Ahn
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Lee R
authors: LR
authors: Hagey
authors: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Casey E
authors: CE
authors: Romanoski
authors: ISIS Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: Richard G
authors: RG
authors: Lee
authors: ISIS Pharmaceuticals, Carlsbad, CA 92010, USA.
authors: Mark J
authors: MJ
authors: Graham
authors: Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku Medical Megabank Organization, Sendai 980-8573, Japan.
authors: Hozumi
authors: H
authors: Motohashi
authors: Department of Medical Biochemistry, Tohoku Medical Megabank Organization, Sendai 980-8573, Japan.
authors: Masayuki
authors: M
authors: Yamamoto
authors: Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA. Electronic address: pedwards@mednet.ucla.edu.
authors: Peter A
authors: PA
authors: Edwards
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000378:metabolism*; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D006801:Humans; D051259:MafG Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
chemical_list: D001647:Bile Acids and Salts; D051259:MafG Transcription Factor
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