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.

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