Bile acid composition and insulin sensitivity

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PROJECT SUMMARY Bile acid composition contributes strongly to metabolic regulation. The particular subset of bile acids that are hydroxylated in the carbon 12? position (12HBAs) are negatively regulated by insulin signaling and synthesized at higher rates in people with insulin resistance. People with low 12HBAs show improvements in glucose and lipid metabolism, but the mechanisms of these effects are unknown. A longstanding barrier to progress in understanding the mechanisms by which bile acid composition regulates systemic metabolism has been the lack of a translationally relevant mouse model. But exciting recent progress in the field has uncovered mouse models with humanized bile acid composition. In this grant, we will use humanized mice to dissect the physiologic and molecular mechanisms by which bile acid composition, particularly 12HBAs, regulate lipid and glucose metabolism. We will examine effects in the liver, the intestine, and the adipose tissue, three key tissues where 12HBAs may carry out their differential effects. We will complement gold-standard in vivo mouse studies with ex vivo and in vitro systems to isolate the cell autonomous effects of bile acid composition. Success of this work will reveal fundamental mechanisms by which bile acid composition regulates metabolic homeostasis and may inform pharmacologic attempts to specifically reduce 12HBAs for metabolic disease treatment.