Weaving betaKlotho into bile acid metabolism

Bile acids are natural detergents that assist in the absorption and digestion of fats in the intestine. In liver, the synthesis of bile acids from cholesterol is regulated by multiple signaling cascades that repress transcription of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the classic bile acid synthesis pathway. In this issue of the JCI, Ito and coworkers demonstrate that mice lacking betaKlotho, a membrane protein with 2 putative glycosidase domains, have increased Cyp7a1 mRNA levels and bile acid concentrations. betaKlotho-KO mice also have small gallbladders and are resistant to cholesterol gallstone formation. These findings highlight the central role of betaKlotho in bile acid homeostasis and raise the possibility that this protein could be a pharmacologic target for the treatment of gallstones.