Abstract
Cholesterol 7α-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.
Highlights
Cholesterol 7α-hydroxylase plays an important role in maintaining cholesterol homeostasis by catalyzing the rate-limiting step in bile acid biosynthesis from hepatic cholesterol (Myant and Mitropoulos, 1977; Jelinek et al, 1990; Redinger, 2003)
We investigated whether forkhead transcription factor O1 (FOXO1) might participate in the regulation of rat cholesterol 7α-hydroxylase (CYP7A1) transcription to control cholesterol/bile acid metabolisms as well as glucose metabolism in liver, possibly linking the two major metabolic pathways
The results suggest that FOXO1 may modulate CYP7A1 transcriptional activity onto its promoter and peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) co-regulates the CYP7A1 transcription
Summary
Cholesterol 7α-hydroxylase (cytochrome P450 7A1, CYP7A1) plays an important role in maintaining cholesterol homeostasis by catalyzing the rate-limiting step in bile acid biosynthesis from hepatic cholesterol (Myant and Mitropoulos, 1977; Jelinek et al, 1990; Redinger, 2003). CYP7A1 is regulated mainly at the transcription level by various effectors such as diurnal rhythm, stress, xenobiotics, cholesterol, and bile acids, the direct end products of CYP7A1 (Yamagata et al, 2004). Forkhead transcription factor O1 (FOXO1) mediates the important effects of insulin as a member of insulin signaling cascade (Barthel et al, 2005) in liver, pancreas, skeletal muscle, adipose tissue and hypothalamus. In adipose tissue and skeletal muscle, FOXO1 prevents differentiations of preadipocytes and myoblast
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