Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho

We have generated a line of mutant mouse that lacks betaKlotho, a protein that structurally resembles Klotho. The synthesis and excretion of bile acids were found to be dramatically elevated in these mutants, and the expression of 2 key bile acid synthase genes, cholesterol 7alpha-hydroxylase (Cyp7a1) and sterol 12alpha-hydroxylase (Cyp8b1), was strongly upregulated. Nuclear receptor pathways and the enterohepatic circulation, which regulates bile acid synthesis, seemed to be largely intact; however, bile acid-dependent induction of the small heterodimer partner (SHP) NR0B2, a common negative regulator of Cyp7a1 and Cyp8b1, was significantly attenuated. The expression of Cyp7a1 and Cyp8b1 is known to be repressed by dietary bile acids via both SHP-dependent and -independent regulations. Interestingly, the suppression of Cyp7a1 expression by dietary bile acids was impaired, whereas that of Cyp8b1 expression was not substantially altered in betaklotho mice. Therefore, betaKlotho may stand as a novel contributor to Cyp7a1-selective regulation. Additionally, betaKlotho-knockout mice exhibit resistance to gallstone formation, which suggests the potential future clinical relevance of the betaKlotho system.