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Papers In Press, published online ahead of print May 29, 2008
J. Lipid Res., doi:10.1194/jlr.M800140-JLR200
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Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272
Corresponding Author: jchiang{at}neoucom.edu
The transforming growth factor ß1 (TGFß1)/Smad pathway plays a critical role in cholestasis and liver fibrosis. Previous studies show that TGFß1 and proinflammatory cytokines inhibits CYP7A1 gene transcription and bile acid synthesis in human hepatocytes. Insulin is known to play a role in regulating CYP7A1 and bile acid synthesis. In this study, we investigated insulin/FoxO1, TGFß1/Smad3, and tumor necrosis factor a (TNFa)/cJun regulation of rat Cyp7a1 gene transcription. In contrast to strong inhibition of human CYP7A1 gene transcription, TGFß1 stimulates rat Cyp7a1 reporter activity and Smad3 binds to the core promoter of the rat Cyp7a1 gene. Interestingly, Smad3, FoxO1 and HNF4a synergistically stimulated rat Cyp7a1 gene transcription. Disruption of the binding site for Smad3, FoxO1 or HNF4a strongly attenuated the rat Cyp7a1 promoter activity. Furthermore, TNFa and cJun attenuated TGFß1 stimulation of rat Cyp7a1. Insulin or adenovirus-mediated expression of constitutively active AKT1 inhibited FoxO1 and Smad3 synergy. In streptozotocin (STZ)-induced diabetic rats, Cyp7a1 mRNA expression levels were induced and insulin attenuated CYP7A1 mRNA levels. Chromatin immunoprecipitation (ChIP) assay showed that FoxO1 binding to Cyp7a1 chromatin was increased in STZ-treated 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, TGFß and TNFa signaling pathways may regulate bile acid synthesis and lipid homeostasis in diabetes, non-alcoholic fatty liver disease and liver fibrosis.
Revised on May 9, 2008
Accepted on May 28, 2008
Transforming growth factor
1, tumor necrosis factor a, and insulin signaling crosstalk in regulation of the rat cholesterol 7
-hydroxylase gene expression
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