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Journal of Lipid Research, Vol. 49, 1981-1989, September 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

TGFβ1, TNF, and insulin signaling crosstalk in regulation of the rat cholesterol 7-hydroxylase gene expression^*

Tiangang Li, Huiyan Ma and John Y. L. Chiang¹

Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272

^* This study is supported by NIH grants DK58379 and DK44442.

Published, JLR Papers in Press, May 29, 2008.

¹ To whom correspondence should be addressed. e-mail: jchiang{at}neoucom.edu

The TGFβ1/Smad pathway plays a critical role in cholestasis and liver fibrosis. Previous studies show that TGFβ1, TNF, and insulin inhibit cholesterol 7-hydroxylase (CYP7A1) gene transcription and bile acid synthesis in human hepatocytes. In this study, we investigated insulin, TGFβ1, and TNF regulation of rat Cyp7a1 gene transcription. In contrast to inhibition of human CYP7A1 gene transcription, TGFβ1 stimulates rat Cyp7a1 reporter activity. Smad3, FoxO1, and HNF4 synergistically stimulated rat Cyp7a1 gene transcription. Mutations of the Smad3, FoxO1, or HNF4 binding site attenuated the rat Cyp7a1 promoter activity. Furthermore, TNF 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 TNF signaling pathways may regulate bile acid synthesis and lipid homeostasis in diabetes, fatty liver disease, and liver fibrosis.

Supplementary key words CYP7A1 • bile acid synthesis • liver fibrosis • nuclear receptors • Smad • FoxO1 • TGFβ • cholestasis

Abbreviations: AKT/PKB, protein kinase B; BDL, bile duct ligation; ChIP, chromatin immunoprecipitation; CYP7A1, cholesterol 7-hydroxylase; FoxO1, forkhead transcription factor O1; HNF4, hepatocyte nuclear factor 4; HSC, hepatic stellate cells; Smad, mothers against decapentaplegic homolog; STZ, streptozotocin; TGFβ1, transforming growth factor β1; TβRI, TGFβ1 receptor type I; TβRII, TGFβ1 receptor type II; TNF, tumor necrosis factor

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