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Deficiency of Capicua disrupts bile acid homeostasis

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Title
Deficiency of Capicua disrupts bile acid homeostasis
Author(s)
Eunjeong Kim; Sungjun Park; Nahyun Choi; Jieon Lee; Jeehyun Yoe; Soeun Kim; Hoe-Yune Jung; Kyong-Tai Kim; Hyojin Kang; John D. Fryer; Huda Y. Zoghbi; Daehee Hwang; Yoontae Lee
Publication Date
2015-02
Journal
SCIENTIFIC REPORTS, v.5, no., pp.8272 -
Publisher
NATURE PUBLISHING GROUP
Abstract
Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 and cancer in mammals; however, the in vivo physiological functions of CIC remain largely unknown. Here we show that Cic hypomorphic (Cic-L-/-) mice have impaired bile acid (BA) homeostasis associated with induction of proinflammatory cytokines. We discovered that several drug metabolism and BA transporter genes were down-regulated in Cic-L-/- liver, and that BA was increased in the liver and serum whereas bile was decreased within the gallbladder of Cic-L-/- mice. We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L-/- liver. Consistent with this finding, levels of hepatic transcriptional regulators, such as hepatic nuclear factor 1 alpha (HNF1a), CCAAT/enhancer-binding protein beta (C/EBPb), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXRa), were markedly decreased in Cic-L-/- mice. Moreover, induction of tumor necrosis factor alpha (Tnfa) expression and decrease in the levels of FOXA2, C/EBPb, and RXRa were found in Cic-L-/- liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L-/- mice. Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.
URI
http://pr.ibs.re.kr/handle/8788114/1634
DOI
10.1038/srep08272
ISSN
2045-2322
Appears in Collections:
Center for Plant Aging Research (식물 노화·수명 연구단) > Journal Papers (저널논문)
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