Abstract 186: Cyp8b1 Ablation Prevents Western Diet-Induced Weight Gain and Hepatic Steatosis due to Impaired Fat Absorption

Abstract

Bile acids (BAs) are cholesterol derivatives that are well-known for their role in facilitating intestinal lipid absorption. Furthermore, they can regulate glucose and lipid metabolism by activating nuclear and cell surface receptors. Insulin resistance is correlated with alterations in bile acid composition, in particular higher levels of 12α-hydroxylated BAs. These BA species are generated by the enzyme Cyp8b1. We hypothesized that elevated levels of 12α-hydroxylated BAs could be a link between insulin resistance and defects of lipid metabolism. To study the role of Cyp8b1 in the regulation of lipid metabolism, we used Cyp8b1 deficient mice-which are unable to produce 12α-hydroxy BAs-and challenged them with a western type diet. We found that Cyp8b1-/- mice gained less weight compared to controls, which was entirely accounted for by fat mass. Triglyceride and cholesterol accumulation in the liver of Cyp8b1-/- mice were also strongly reduced. We found that these improvements were due to reduced lipid absorption in the intestine of Cyp8b1-/- mice, which could be rescued by replenishing the pool with taurocholic acid. The lipid malabsorption resulted in higher caloric excretion in the feces, due to excess excretion of hydrolyzed dietary lipids. When we fed the mice with a fat-free diet, these differences between genotypes were normalized, confirming the central role of BA composition-not just overall levels-in intestinal lipid absorption and whole-body lipid homeostasis. Based on these findings, it is possible that reducing 12α-hydroxy BAs could be a therapeutic option for the control of obesity and lipid homeostasis.