Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo.
J Biol Chem
; 287(49): 41334-41, 2012 Nov 30.
Article
em En
| MEDLINE
| ID: mdl-23038264
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Colesterol 7-alfa-Hidroxilase
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Regulação da Expressão Gênica
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Receptores Citoplasmáticos e Nucleares
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Fator 4 Nuclear de Hepatócito
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article