Liver-specific ablation of Krüppel-associated box–associated protein 1 in mice leads to male-predominant hepatosteatosis and development of liver adenoma

Authors

  • Karolina Bojkowska,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Fabio Aloisio,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. School of Veterinary Medicine, University of Bern, Bern, Switzerland
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  • Marco Cassano,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Adamandia Kapopoulou,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. Swiss Institute of Bioinformatics, Lausanne, Switzerland
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  • Francesca Santoni de Sio,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Nadine Zangger,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Sandra Offner,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Cristina Cartoni,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Charles Thomas,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Simon Quenneville,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Kai Johnsson,

    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    3. “Chemical Biology” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Didier Trono

    Corresponding author
    1. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    2. “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    • Ecole Polytechnique Fédérale de Lausanne SV-DO, Bâtiment SV, Station 19, CH-1015 Lausanne, Switzerland
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    • fax: +41 21 693 95 38


  • Potential conflict of interest: Nothing to report.

Abstract

The liver is characterized by sexually dimorphic gene expression translating into sex-specific differences in lipid, drug, steroid hormone, and xenobiotic metabolism, with distinct responses of males and females to environmental challenges. Here, we investigated the role of the Krüppel-associated box (KRAB)-associated protein 1 (KAP1) epigenetic regulator in this process. Liver-specific KAP1 knockout (KO) led to strikingly sexually dimorphic phenotypic disturbances, including male-predominant steatosis and hepatic tumors with up-regulation of protein kinase B and extracellular signal-related kinases 1/2 mitogen-activated protein kinase signaling. This correlated with the sex-specific transcriptional dysregulation of a wide range of metabolic genes, notably those involved in retinol and sex hormone processing as well as in detoxification. Furthermore, chromatin immunoprecipitation followed by deep sequencing indicated that a number of dysregulated genes are direct targets of the KRAB/KAP1 repression system. Those genes include sexually dimorphic cytochrome P 450 Cyp2d9, glutathione S-transferase π, Cyp2a, Cyp2b, and Cyp3a gene clusters. Additionally, we identified a male-restricted KAP1-binding site in the fat-specific protein 27 gene, correlating with its male-predominant up-regulation upon Kap1 deletion, suggesting that the latter might be an important trigger in the development of male-specific hepatosteatosis and secondary tumorigenesis. Conclusion: This work reveals KRAB/KAP1-mediated transcriptional regulation as a central event in metabolic control hormones, drugs, and xenobiotics in the liver and further links disturbances in these processes with hepatic carcinogenesis. (HEPATOLOGY 2012)

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