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

doi:10.1074/jbc.m112.421834

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.

Highlights

Fibroblast growth factor 19 (FGF19) inhibits bile acid synthesis by repressing transcription of Cyp7a1 through a small heterodimer partner (SHP)-dependent mechanism
In a series of in vivo loss-of-function studies, we have examined the roles of liver receptor homolog-1 (LRH-1) and hepatocyte nuclear factor 4␣ (HNF4␣), another nuclear receptor implicated in bile acid homeostasis [17, 18], in regulating Cyp7a1
HNF4␣ and LRH-1 Recruit SHP to the Cyp7a1 Promoter—It was previously shown that FGF15 overexpression fails to repress Cyp7a1 transcription in ShpϪ/Ϫ mice [8]

Summary

Background

FGF19 inhibits bile acid synthesis by repressing transcription of Cyp7a1 through a SHP-dependent mechanism. FGF19 inhibits bile acid synthesis in liver through transcriptional repression of cholesterol 7␣-hydroxylase (CYP7A1) via a mechanism involving the nuclear receptor SHP. In a series of loss-offunction studies, we show that the nuclear receptors HNF4␣ and LRH-1 have dual roles in regulating Cyp7a1 in vivo. They cooperate in maintaining basal Cyp7a1 expression. They enable SHP binding to the Cyp7a1 promoter and facilitate FGF19mediated repression of bile acid synthesis. In a series of in vivo loss-of-function studies, we have examined the roles of LRH-1 and hepatocyte nuclear factor 4␣ (HNF4␣), another nuclear receptor implicated in bile acid homeostasis [17, 18], in regulating Cyp7a1. Using acute conditional knock-out mouse models, we show that both LRH-1 and HNF4␣ are crucial transcriptional activators of the Cyp7a1 promoter and are required for FGF19 and SHP to repress Cyp7a1

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION