Insulin regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c.

Title

Insulin regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c.

Creator

Li Tiangang; Kong Xiaoying; Owsley Erika; Ellis Ewa; Strom Stephen; Chiang John Y L

Publisher

The Journal of biological chemistry

Date

2006
2006-09

Description

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 7alpha-hydroxylase gene expression in human hepatocytes. Real-time PCR assays showed that physiological concentrations of insulin rapidly stimulated cholesterol 7alpha-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 4alpha and peroxisome proliferator-activated receptor gamma coactivator-1alpha 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 gamma-coactivator-1alpha 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.

Subject

*Gene Expression Regulation; *Transcriptional Activation; Adolescent; Adult; Animals; Child; Cholesterol 7-alpha-Hydroxylase/*biosynthesis/genetics; Enzymologic; Female; Forkhead Box Protein O1; Forkhead Transcription Factors/*physiology; Hepatocytes/*enzymology; Humans; Insulin/metabolism/*physiology; Male; Middle Aged; Preschool; Rats; Sterol Regulatory Element Binding Protein 1/*physiology; Transcription Factors/*physiology

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

28745–28754

Issue

39

Volume

281

Citation

Li Tiangang; Kong Xiaoying; Owsley Erika; Ellis Ewa; Strom Stephen; Chiang John Y L, “Insulin regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c.,” NEOMED Bibliography Database, accessed September 25, 2021, https://neomed.omeka.net/items/show/4074.

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