IMPACT OF THE BILE ACID GENE CYP8B1 ON GLUCOSE METABOLISM IN HUMANS AND MICE

Abstract

CYP8B1 acts in the bile acid (BA) synthesis pathway to generate 12α-hydroxylated BAs which are associated with insulin resistance in humans. To determine if reduced CYP8B1 activity improves insulin sensitivity, we identified carriers of loss-of-function mutations in CYP8B1 and characterized their glucose metabolic phenotypes. We found that plasma 12α-hydroxylated:non-12α-hydroxylated BA ratio was significantly lower in heterozygous CYP8B1 mutation carriers. Mixed meal tolerance testing demonstrated lower insulin levels, and hyperinsulinemic-euglycemic clamps showed higher insulin sensitivity index and higher glucose infusion rate in the carriers, indicating increased insulin sensitivity. In vitro studies of muscle insulin signalling in response to the altered BA composition demonstrated FOXO1-mediated upregulation of insulin receptor expression and increased muscle glucose uptake. We observed similar phenotypes in Cyp8b1-/- mice, which showed increased insulin sensitivity and increased peripheral glucose disposal. Our study has demonstrated that decreased CYP8B1 activity increases insulin sensitivity in humans and mice, mediated through altered BA signalling.