Deficiency of Capicua disrupts bile acid homeostasis.
Deficiency of Capicua disrupts bile acid homeostasis.
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DOI：
10.1038/srep08272
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发表时间：
2015-02-05
影响因子：
4.6
通讯作者：
Lee Y
中科院分区：
文献类型：
--
作者：
Kim E;Park S;Choi N;Lee J;Yoe J;Kim S;Jung HY;Kim KT;Kang H;Fryer JD;Zoghbi HY;Hwang D;Lee Y
Capicua（CIC）与哺乳动物脊髓小脑共济失调1型和癌症的发病机制有关，然而，CIC在体内的生理功能仍不清楚。在这里，我们表明，Cic hypomorphic（Cic-L-/-）小鼠有受损的胆汁酸（BA）的体内平衡与诱导的促炎细胞因子。我们发现，Cic-L-/-小鼠肝脏中的几种药物代谢和BA转运蛋白基因下调，并且Cic-L-/-小鼠肝脏和血清中的BA增加，而胆囊中的胆汁减少。我们还发现Cic-L-/-肝脏中促炎细胞因子基因的水平上调。与这一发现一致，Cic-L-/-小鼠中肝脏转录调节因子的水平，如肝核因子1 α（HNF 1 α）、CCAAT/增强子结合蛋白β（C/EBP β）、叉头盒蛋白A2（FOXA 2）和类维生素A X受体α（RXR α）显著降低。此外，在BA积聚之前，Cic-L-/-肝脏中发现肿瘤坏死因子α（Tnf α）表达诱导以及FOXA 2、C/EBP β和RXR α水平下降，这表明炎症可能是Cic-L-/-小鼠胆汁淤积的原因。我们的研究结果表明，CIC是一个关键的调节BA的稳态，其功能障碍可能与慢性肝病和代谢紊乱。
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 (HNF1α), CCAAT/enhancer-binding protein beta (C/EBPβ), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXRα), were markedly decreased in Cic-L-/- mice. Moreover, induction of tumor necrosis factor alpha (Tnfα) expression and decrease in the levels of FOXA2, C/EBPβ, and RXRα 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.