Young-Chae Kim1, Sungsoon Fang1,2, Sangwon Byun1, Sunmi Seok1, Byron Kemper1 and Jongsook KimKemper1,*
1 Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL
2 Current address: Gene Expression Laboratory, Salk Institute, La Jolla, CA
*To whom correspondence should be addressed: J. Kim Kemper, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 407 S. Goodwin Avenue, Urbana, IL 61801.
Bile acids (BAs) function as endocrine signaling molecules that activate multiple nuclear and membrane receptor signaling pathways to control fed-state metabolism. Since the detergent-like property of BAs causes liver damage at high concentrations, hepatic BA levels must be tightly regulated. BA homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary bile acid receptor, farnesoid X receptor (FXR), and small heterodimer partner (SHP) that inhibits BA synthesis by recruiting repressive histone-modifying enzymes. Although histone modifiers have been shown to regulate BA-responsive genes, their in vivo functions remain unclear. Here we show that lysine-specific histone demethylase1 (LSD1) is directly induced by BA-activated FXR, is recruited to BA synthetic genes, Cyp7a1 and Cyp8b1, and the BA uptake transporter gene, Ntcp, and removes a gene-activation mark, tri-methylated histone H3 lysine-4, leading to gene repression. LSD1 recruitment was dependent on SHP, and LSD1-mediated demethylation of H3K4-me3 was required for additional repressive histone modifications, H3K9/K14 deacetylation and H3K9 methylation. BA overload, feeding 0.5% cholic acid chow for 6 days, resulted in adaptive responses of altered expression of hepatic genes involved in BA synthesis, transport, and detoxification/conjugation. In contrast, adenoviral-mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum AST/ALT levels, and hepatic inflammation. This study identifies LSD1 as a novel histone-modifying enzyme in the orchestrated regulation mediated by the FXR and SHP that reduces hepatic BA levels and protects the liver against BA toxicity. This article is protected by copyright. All rights reserved.
Keywords: SHP; epigenomic regulation; Cyp7a1; Ntcp; cholestasis