Exp Mol Med.  2011 Oct;43(10):571-579. 10.3858/emm.2011.43.10.064.

Insulin-dependent suppression of cholesterol 7alpha-hydroxlase is a possible link between glucose and cholesterol metabolisms

• Park WH
• Pak YK

• KMID: 1123369
• DOI: http://doi.org/10.3858/emm.2011.43.10.064

Abstract

Cholesterol 7alpha-hydroxylase (CYP7A1) regulates the balance between cholesterol supply and metabolism by catalyzing the rate-limiting step of bile acid biosynthesis. The transcriptional activity of CYP7A1 is tightly controlled by various nuclear receptors. A forkhead transcription factor O1 (FOXO1) plays a critical role in metabolism, and insulin inactivates FOXO1 through Akt-dependent phosphorylation and nuclear exclusion. We investigated the role of insulin-Akt-FOXO1 signaling pathway in CYP7A1 transcriptional regulation since we found putative insulin-response elements, FOXO1 binding sequences, in both rat and human CYP7A1 promoters. However, ectopic expression of FOXO1 increased the rat CYP7A1-, but mildly reduced human CYP7A1-promoter activities in a dose-dependent manner. Similarly to bile acids, insulin treatment increased small heterodimer partner (SHP) mRNA rapidly and transiently, leading to the suppression of CYP7A1 transcription in both human and rodents. Chromatin immunoprecipitation showed that FOXO1 directly bound to rat CYP1A1 promoter in the absence of insulin. FOXO1 binding to the rat promoter was diminished by insulin treatment as well as by expression of SHP. Our results suggest that the stimulation of insulin- signaling pathway of Akt-FOXO1 and SHP expression may regulate cholesterol/bile acid metabolisms in liver, linking carbohydrate and cholesterol metabolic pathways. A prolonged exposure of insulin in hyperinsulinemic insulin resistance or diabetic status represses CYP7A1 transcription and bile acid biosynthesis through SHP induction and FOXO1 inactivation, leading to impairment of the hepatic cholesterol/bile acid metabolisms.

Keyword

cholesterol; cholesterol 7-alpha-hydroxylase; forkhead transcription factors; gene expression regulation; nuclear receptor subfamily 0, group B, member 2

MeSH Terms

Animals
Bile Acids and Salts/metabolism
Cholesterol/*metabolism
Cholesterol 7-alpha-Hydroxylase/genetics/*metabolism
Forkhead Transcription Factors/genetics/*metabolism
Gene Expression Regulation/drug effects
Glucose/*metabolism
Hep G2 Cells
Humans
Insulin/pharmacology
Lipid Metabolism/drug effects
Liver/*metabolism/pathology
Mice
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Nerve Tissue Proteins/genetics/*metabolism
Protein Binding/drug effects/genetics
Proto-Oncogene Proteins c-akt/metabolism
Rats
Receptors, Cytoplasmic and Nuclear/genetics/metabolism
Sequence Deletion/genetics
Signal Transduction/drug effects/genetics
Transcriptional Activation/drug effects/genetics