Insulin Regulation of Cholesterol 7α-Hydroxylase Expression in Human Hepatocytes

• Published in: The Journal of biological chemistry Vol. 281; no. 39; p. 28745
• Main Authors: Tiangang Li, Xiaoying Kong, Erika Owsley, Ewa Ellis, Stephen Strom, John Y. L. Chiang
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 29.09.2006
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M605815200

Bile acid synthesis and pool size increases in diabetes, whereas insulin inhibits bile acid synthesis. The objective of this study is to elucidate the mechanism of insulin regulation of cholesterol 7α-hydroxylase gene expression in human hepatocytes. Real-time PCR assays showed that physiological concentrations of insulin rapidly stimulated cholesterol 7α-hydroxylase (CYP7A1) mRNA expression in primary human hepatocytes but inhibited CYP7A1 expression after extended treatment. The insulin-regulated forkhead box O1 (FoxO1) and steroid regulatory element-binding protein-1c (SREBP-1c) strongly inhibited hepatocyte nuclear factor 4α and peroxisome proliferator-activated receptor γ coactivator-1α trans-activation of the CYP7A1 gene. FoxO1 binds to an insulin response element in the rat CYP7A1 promoter, which is not present in the human CYP7A1 gene. Insulin rapidly phosphorylates and inactivates FoxO1, whereas insulin induces nuclear SREBP-1c expression in human primary hepatocytes. Chromatin immunoprecipitation assay shows that insulin reduced FoxO1 and peroxisome proliferators-activated receptor γ-coactivator-1α but increased SREBP-1c recruitment to CYP7A1 chromatin. We conclude that insulin has dual effects on human CYP7A1 gene transcription; physiological concentrations of insulin rapidly inhibit FoxO1 activity leading to stimulation of the human CYP7A1 gene, whereas prolonged insulin treatment induces SREBP-1c, which inhibits human CYP7A1 gene transcription. Insulin may play a major role in the regulation of bile acid synthesis and dyslipidemia in diabetes.