Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo

Serkan Kir, Yuan Zhang, Robert D. Gerard, Steven A. Kliewer, David J. Mangelsdorf

Research output: Contribution to journalArticle

67 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)41334-41341
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number49
DOIs
StatePublished - Nov 30 2012

Fingerprint

Fibroblast Growth Factors
Cytoplasmic and Nuclear Receptors
Bile Acids and Salts
Transcription
Histone Code
Cholesterol 7-alpha-Hydroxylase
Ileum
Liver
Histones

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo. / Kir, Serkan; Zhang, Yuan; Gerard, Robert D.; Kliewer, Steven A.; Mangelsdorf, David J.

In: Journal of Biological Chemistry, Vol. 287, No. 49, 30.11.2012, p. 41334-41341.

Research output: Contribution to journalArticle

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