title: Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo.
abstract: Fibroblast growth factor 19 (FGF19) is a postprandial enterokine induced by the nuclear bile acid receptor, FXR, in ileum. FGF19 inhibits bile acid synthesis in liver through transcriptional repression of cholesterol 7α-hydroxylase (CYP7A1) via a mechanism involving the nuclear receptor SHP. Here, in a series of loss-of-function studies, we show that the nuclear receptors HNF4α and LRH-1 have dual roles in regulating Cyp7a1 in vivo. First, they cooperate in maintaining basal Cyp7a1 expression. Second, they enable SHP binding to the Cyp7a1 promoter and facilitate FGF19-mediated repression of bile acid synthesis. HNF4α and LRH-1 promote active transcription histone marks on the Cyp7a1 promoter that are reversed by FGF19 in a SHP-dependent manner. These findings demonstrate that both HNF4α and LRH-1 are important regulators of Cyp7a1 transcription in vivo.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Serkan
authors.initials: S
authors.lastname: Kir
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001665:Binding Sites; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D001647:Bile Acids and Salts; C117476:FGF19 protein, human; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; C496593:Hnf4a protein, mouse; C082631:NR5A2 protein, human; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6