Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho
Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho
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DOI：
10.1172/jci23076
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发表时间：
2005-08-01
影响因子：
15.9
通讯作者：
Nabeshima, Y
中科院分区：
文献类型：
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作者：
Ito, S;Fujimori, T;Nabeshima, Y
我们已经产生了一种缺乏β Klotho的突变小鼠，β Klotho是一种结构上类似Klotho的蛋白质。胆汁酸的合成和排泄被发现在这些突变体中显著升高，并且2个关键胆汁酸合酶基因胆固醇7 α-羟化酶（Cyp 7a 1）和固醇12 α-羟化酶（Cyp 8b 1）的表达被强烈上调。核受体途径和肠肝循环，调节胆汁酸的合成，似乎在很大程度上是完整的，但是，胆汁酸依赖性诱导的小异源二聚体伴侣（SHP）NR 0 B2，一个共同的负调节Cyp 7a 1和Cyp 8b 1，显着减弱。Cyp 7a 1和Cyp 8b 1的表达已知通过SHP依赖性和非依赖性调节被膳食胆汁酸抑制。有趣的是，饮食胆汁酸对Cyp 7a 1表达的抑制被削弱，而Cyp 8b 1表达在β klotho（-/-）小鼠中没有实质性改变。因此，β Klotho可能是Cyp 7a 1选择性调节的新贡献者。此外，β Klotho基因敲除小鼠表现出对胆结石形成的抗性，这表明β Klotho系统的潜在未来临床相关性。
We have generated a line of mutant mouse that lacks beta Klotho, 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 7 alpha-hydroxylase (Cyp7a1) and sterol 12 alpha-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 beta klotho(-/-) mice. Therefore, beta Klotho may stand as a novel contributor to Cyp7a1-selective regulation. Additionally, beta Klotho-knockout mice exhibit resistance to gallstone formation, which suggests the potential future clinical relevance of the beta Klotho system.