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Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho
Shinji Ito, … , Yoko Nabeshima, Yo-ichi Nabeshima
Shinji Ito, … , Yoko Nabeshima, Yo-ichi Nabeshima
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2202-2208. https://doi.org/10.1172/JCI23076.
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Research Article Cardiology Article has an altmetric score of 9

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

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Abstract

We have generated a line of mutant mouse that lacks βKlotho, 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 7α-hydroxylase (Cyp7a1) and sterol 12α-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 βklotho–/– mice. Therefore, βKlotho may stand as a novel contributor to Cyp7a1-selective regulation. Additionally, βKlotho-knockout mice exhibit resistance to gallstone formation, which suggests the potential future clinical relevance of the βKlotho system.

Authors

Shinji Ito, Toshihiko Fujimori, Akiko Furuya, Junko Satoh, Yoko Nabeshima, Yo-ichi Nabeshima

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Figure 1

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Targeted disruption of the βklotho gene. (A) Strategy for disruption of ...
Targeted disruption of the βklotho gene. (A) Strategy for disruption of mouse βklotho locus. Schematic diagrams of the targeting vector (top), wild-type allele (middle), and disrupted allele (bottom) are shown. Numbers correspond to the distance (bp) from the putative translation initiation site. The probe used for Southern blot analysis is shown at the bottom. (B) Southern blot analysis of EcoRV-digested genomic DNA. Blots were hybridized with the probe indicated in A. (C) Northern blot analysis of βklotho gene expression in the liver. The βklotho-specific probe hybridizes with 2 species of transcripts (1). (D) Western blot analysis of βKlotho protein expression. Total proteins (15 μg) extracted from indicated tissues were blotted on a PVDF membrane and incubated with a βKlotho-specific monoclonal antibody. βKlotho protein was detected only in βklotho-expressing tissues of wild-type mice and was absent in tissues of βklotho–/– mice. WAT, white adipose tissue. (E) Growth curve comparison of βklotho+/+, βklotho+/–, and βklotho–/– mice. Body weights were traced in mice from ages 2 to 6 weeks. Five to 12 mice for each group were examined. Error bars indicate SD. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 28 patents
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