title: Deficiency of Capicua disrupts bile acid homeostasis.
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 (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.
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Eunjeong
authors: E
authors: Kim
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Sungjun
authors: S
authors: Park
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Nahyun
authors: N
authors: Choi
authors: Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Jieon
authors: J
authors: Lee
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Jeehyun
authors: J
authors: Yoe
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Soeun
authors: S
authors: Kim
authors: Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Hoe-Yune
authors: HY
authors: Jung
authors: 1] Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea [2] Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Kyong-Tai
authors: KT
authors: Kim
authors: National Institute of Supercomputing and Networking, Korea Institute of Science and Technology Information, Daejeon 305-806, Republic of Korea.
authors: Hyojin
authors: H
authors: Kang
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: John D
authors: JD
authors: Fryer
authors: Howard Hughes Medical Institute, Departments of Molecular and Human Genetics, and Neuroscience, Baylor College of Medicine, and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
authors: Huda Y
authors: HY
authors: Zoghbi
authors: 1] Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea [2] Center for Plant Aging Research, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu, 711-873, Republic of Korea.
authors: Daehee
authors: D
authors: Hwang
authors: 1] Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea [2] Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors: Yoontae
authors: Y
authors: Lee
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001774:Blood Chemical Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006706:Homeostasis / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012097:Repressor Proteins / Q000172:deficiency*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; C498611:Cic protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D012097:Repressor Proteins; D014157:Transcription Factors
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