title: Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity.
abstract: 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. Bile acid homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary BA receptor, farnesoid X receptor, and small heterodimer partner, which 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 farnesoid X receptor, is recruited to the BA synthetic genes Cyp7a1 and Cyp8b1 and the BA uptake transporter gene Ntcp, and removes a gene-activation marker, trimethylated histone H3 lysine-4, leading to gene repression. Recruitment of LSD1 was dependent on small heterodimer partner, and LSD1-mediated demethylation of trimethylated histone H3 lysine-4 was required for additional repressive histone modifications, acetylated histone 3 on lysine 9 and 14 deacetylation, and acetylated histone 3 on lysine 9 methylation. A 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, adenovirus-mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum alanine aminotransferase and aspartate aminotransferase levels, and hepatic inflammation.
  
  
  CONCLUSIONS
  This study identifies LSD1 as a novel histone-modifying enzyme in the orchestrated regulation mediated by the farnesoid X receptor and small heterodimer partner that reduces hepatic BA levels and protects the liver against BA toxicity.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Sungsoon
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Sangwon
authors.initials: S
authors.lastname: Byun
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Sunmi
authors.initials: S
authors.lastname: Seok
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Byron
authors.initials: B
authors.lastname: Kemper
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D056466:Histone Demethylases / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D056466:Histone Demethylases; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C504076:KDM1a protein, mouse