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

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