Abstract

The level and composition of bile acids (BAs) play a crucial role in lipid and fat absorption and metabolism, which then impacts metabolic diseases such as Type 2 diabetes (T2D). BAs are amphipathic molecules synthesized from cholesterol primarily in the liver. The enzyme cytochrome P450 family 8 subfamily B member 1 (CYP8B1), also known as sterol 12α-hydroxylase, is at the branching point of BA biosynthesis. CYP8B1 activity increases the ratio of 12α-OH to non-12α-OH BAs, which is linked to metabolic diseases like obesity and diabetes. We demonstrated that obese mice expressed CYP8B1 at a higher level relative to the lean mice, and that Cyp8b1-/- mice had a reduced 12α-OH/non-12α-OH BAs ratio, improved insulin sensitivity and lipid and glucose metabolism. Moreover, clinical studies revealed that complete loss-of-function mutations in CYP8B1 gene improved insulin sensitivity in individuals, suggesting that CYP8B1 has a regulatory function that could impact T2D. Interestingly, other data suggest that BAs are directly involved in the pathogenesis of diabetic kidney disease (DKD). However, the crosstalk between liver and kidneys via CYP8B1–BAs–BA receptors has not been explored. Given this, it becomes important to determine the activity of the BA receptors in the presence and absence of CYP8B1 activity.

The goal of this proposed study is to identify the role of CYP8B1 in DKD condition. Expanding on this to encompass CYP8B1 in T2D and renal complication will provide a more comprehensive understanding of the BA pathway.