Abstract 1720: Foxo1 and TGFβ1 Signaling Inhibit Cholesterol 7α-Hydroxylase Gene Expression and Bile Acid Synthesis in High Fat Diet Induced Diabetes
Insulin resistance is closely associated with diabetic dyslipidemia characterized by hypercholesterolemia and hypertriglyceridemia. Bile acids are important metabolic regulators of triglyceride and glucose metabolism in the liver. In diabetes, lipid and glucose metabolisms are dysregulated. We reported previously that insulin-regulated FoxO1 transcription factor inhibited transcription of the gene encoding cholesterol 7α-hydroxylase (CYP7A1), a rate-limiting enzyme that converts cholesterol to bile acids in the liver. to investigate the molecular basis for insulin regulation of the CYP7A1 gene in diabetes. Adenovirus mediated expression of a constitutively active form of FoxO1 inhibited CYP7A1 mRNA expression by ~ 70% (n = 7, p < 0.05) and bile acid synthesis by ~ 50% (n = 3, p < 0.05) in human primary hepatocytes, while knocking down of FoxO1 by RNA interference resulted in a ~6-fold induction of CYP7A1 mRNA (n = 4, p < 0.05). At molecular level, FoxO1 interacted with HNF4α and blocked HNF4α recruitment of its co-activator PGC-1α to CYP7A1 chromatin and resulted in inhibition of CYP7A1 gene expression. Physiological concentration of insulin caused rapid FoxO1 nuclear exclusion and resulted in induction of CYP7A1 mRNA expression, but constitutively active FoxO1 blocked insulin induction of CYP7A1. Furthermore, TGFβ 1 repressed CYP7A1 mRNA and antagonized insulin induction of CYP7A1 mRNA expression. In high fat diet-induced mouse model of diabetes and insulin resistance, CYP7A1 mRNA was repressed by ~60% (n = 3, p < 0.05), which correlated with increased hepatic FoxO1 and TGFβ1 expression. FoxO1 is a key regulator that mediates insulin regulation of CYP7A1 and bile acid synthesis. In diabetes, insulin resistance causes increased FoxO1 activity and activation of TGFβ1 signaling to down-regulate CYP7A1 and disrupt bile acid homeostasis.
This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).