期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 49, 页码 41334-41341出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.421834
关键词
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资金
- Howard Hughes Medical Institute
- National Institutes of Health [DK67158, DK62434]
- Robert A. Welch Foundation [I-1275, I-1588]
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 7 alpha-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 HNF4 alpha 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. HNF4 alpha 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 HNF4 alpha and LRH-1 are important regulators of Cyp7a1 transcription in vivo.
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