文章基本信息

标题：TGFβ1, TNFα, and insulin signaling crosstalk in regulation of the rat cholesterol 7α-hydroxylase gene expression
本地全文：下载
作者：Tiangang Li ; Huiyan Ma ; John Y. L. Chiang 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2008
卷号：49
期号：9
页码：1981-1989
DOI：10.1194/jlr.M800140-JLR200
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：The TGFβ1/Smad pathway plays a critical role in cholestasis and liver fibrosis. Previous studies show that TGFβ1, TNFα, and insulin inhibit cholesterol 7α-hydroxylase (CYP7A1) gene transcription and bile acid synthesis in human hepatocytes. In this study, we investigated insulin, TGFβ1, and TNFα regulation of rat Cyp7a1 gene transcription. In contrast to inhibition of human CYP7A1 gene transcription, TGFβ1 stimulates rat Cyp7a1 reporter activity. Smad3, FoxO1, and HNF4α synergistically stimulated rat Cyp7a1 gene transcription. Mutations of the Smad3, FoxO1, or HNF4α binding site attenuated the rat Cyp7a1 promoter activity. Furthermore, TNFα and cJun attenuated TGFβ1 stimulation of rat Cyp7a1. Insulin or adenovirus-mediated expression of constitutively active AKT1 inhibited FoxO1 and Smad3 synergy. In streptozotocin-induced diabetic rats, Cyp7a1 mRNA expression levels were induced and insulin attenuated CYP7A1 mRNA levels. Chromatin immunoprecipitation assay showed that FoxO1 binding to Cyp7a1 chromatin was increased in diabetic rat livers and insulin reduced FoxO1 binding. These results suggest a mechanistic basis for induction of Cyp7a1 activity and bile acid synthesis in cholestatic rats and in diabetic rats. The crosstalk of insulin, TGFβ and TNFα signaling pathways may regulate bile acid synthesis and lipid homeostasis in diabetes, fatty liver disease, and liver fibrosis.