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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bile Acids and Salts / metabolism
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Binding Sites
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Cholesterol 7-alpha-Hydroxylase / biosynthesis*
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Fibroblast Growth Factors / metabolism
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Gene Expression Regulation*
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HEK293 Cells
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Hepatocyte Nuclear Factor 4 / physiology*
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Histones / metabolism
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Humans
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Liver / metabolism
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Mice
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Promoter Regions, Genetic
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology*
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Transcription, Genetic
Substances
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Bile Acids and Salts
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FGF19 protein, human
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HNF4A protein, human
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Hepatocyte Nuclear Factor 4
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Histones
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Hnf4a protein, mouse
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NR5A2 protein, human
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Nr5a2 protein, mouse
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Receptors, Cytoplasmic and Nuclear
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fibroblast growth factor 15, mouse
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Fibroblast Growth Factors
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CYP7A1 protein, human
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Cholesterol 7-alpha-Hydroxylase
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Cyp7a1 protein, mouse
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Protein Tyrosine Phosphatase, Non-Receptor Type 6