Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice.

Title

Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice.

Creator

Li Tiangang; Ma Huiyan; Park Young Joo; Lee Yoon-Kwang; Strom Stephen; Moore David D; Chiang John Y L

Publisher

Biochimica et biophysica acta

Date

2009
2009-10

Description

The conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism. Bile acids are metabolic regulators of triglycerides and glucose metabolism in the liver. This study investigated the roles of FoxO1 in the regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in primary human hepatocytes. Adenovirus-mediated expression of a phosphorylation defective and constitutively active form of FoxO1 (FoxO1-ADA) inhibited CYP7A1 mRNA expression and bile acid synthesis, while siRNA knockdown of FoxO1 resulted in a approximately 6-fold induction of CYP7A1 mRNA in human hepatocytes. Insulin caused rapid exclusion of FoxO1 from the nucleus and resulted in the induction of CYP7A1 mRNA expression, which was blocked by FoxO1-ADA. In high fat diet-fed mice, CYP7A1 mRNA expression was repressed and inversely correlated to increase hepatic FoxO1 mRNA expression and FoxO1 nuclear retention. In conclusion, our current study provides direct evidence that FoxO1 is a strong repressor of CYP7A1 gene expression and bile acid synthesis. Impaired regulation of FoxO1 may cause down-regulation of CYP7A1 gene expression and contribute to dyslipidemia in insulin resistance.

Subject

Adenoviridae/genetics; Animals; Bile Acids and Salts/biosynthesis; Cell Line; Cell Nucleus/drug effects/metabolism; Cholesterol 7-alpha-Hydroxylase/*antagonists & inhibitors/genetics/metabolism; Dietary Fats/*administration & dosage/*pharmacology; Down-Regulation/drug effects; Enzymologic/drug effects; Feeding Behavior/*drug effects; Forkhead Box Protein O1; Forkhead Transcription Factors/genetics/*metabolism; Gene Expression Regulation; Gene Knockdown Techniques; Gene Transfer Techniques; Hepatocytes/drug effects/*enzymology; Humans; Inbred C57BL; Insulin Resistance; Insulin/metabolism; Male; Messenger/genetics/metabolism; Mice; RNA; RNA Interference/drug effects; Tumor

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

991–996

Issue

10

Volume

1791

Citation

Li Tiangang; Ma Huiyan; Park Young Joo; Lee Yoon-Kwang; Strom Stephen; Moore David D; Chiang John Y L, “Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice.,” NEOMED Bibliography Database, accessed April 20, 2021, https://neomed.omeka.net/items/show/3475.

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