Nuclear Receptors HNF4α and LRH-1 Cooperate in Regulating Cyp7a1 in Vivo*

Abstract

Background: FGF19 inhibits bile acid synthesis by repressing transcription of Cyp7a1 through a SHP-dependent mechanism.

Results: Eliminating HNF4α or LRH-1 in liver reduces basal Cyp7a1 expression and disrupts its repression by FGF19 and SHP.

Conclusion: HNF4α and LRH-1 cooperate in regulating basal Cyp7a1 transcription and its repression by FGF19.

Significance: Understanding how bile acid synthesis is repressed has implications for treating chronic diarrhea syndromes.

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.