Besides their role in facilitating lipid absorption, bile acids are increasingly being recognized as signaling molecules that activate cell-signaling receptors. Targeted disruption of cytochrome P450 sterol 12α- hydroxylase (Cyp8b1) results in complete absence of cholic acid and its derivatives. The impact of Cyp8b1 deletion has predominantly been studied with respect to development of atherosclerosis and lipid and bile acid metabolism. Here, for the first time, we investigate the impact of Cyp8b1 deletion on glucose homeostasis. Absence of Cyp8b1 results in improved glucose tolerance, enhanced insulin sensitivity and improved β-cell function in Cyp8b1-/- mice. In addition, our results show that reduced intestinal fat absorption in the absence of biliary cholic acid in Cyp8b1-/- mice leads to increase in free fatty acids reaching the ileal L-cells. This increase in the luminal free fatty acids correlated with significantly increased secretion of the incretin hormone, glucagon like peptide-1 (GLP-1). GLP-1 in turn increases the biosynthesis and secretion of insulin from β-cells, leading to the improved glucose tolerance observed in the Cyp8b1-/- mice. Treatment of Cyp8b1-/- mice with Exendin (9-39) amide, a potent and selective GLP-1 receptor antagonist, restored their glucose tolerance to control levels. Furthermore, cholic acid feeding in Cyp8b1-/- mice resulted in complete normalization of not only fat and glucose tolerance, but also GLP-1 secretion. These data suggest that the absence of cholic acid leads to the improvement in the glycemic control of Cyp8b1-/- mice. Thus, our data demonstrates the importance of Cyp8b1 inhibition in the regulation of glucose metabolism.Medicine, Faculty ofMedical Genetics, Department ofGraduat
