Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance

Authors

  • Xin-An Wang,

    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
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    • These authors contributed equally to this work.

  • Ran Zhang,

    1. State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
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    • These authors contributed equally to this work.

  • Zhi-Gang She,

    1. Sanford-Burnham Medical Research Institute, Cancer Center, La Jolla, CA, USA
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    • These authors contributed equally to this work.

  • Xiao-Fei Zhang,

    1. College of Life Sciences, Wuhan University, Wuhan, P.R. China
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  • Ding-Sheng Jiang,

    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
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  • Tao Wang,

    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
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  • Lu Gao,

    1. Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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  • Wei Deng,

    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
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  • Shu-Min Zhang,

    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
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  • Li-Hua Zhu,

    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
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  • Sen Guo,

    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
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  • Ke Chen,

    1. College of Life Sciences, Wuhan University, Wuhan, P.R. China
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  • Xiao-Dong Zhang,

    1. College of Life Sciences, Wuhan University, Wuhan, P.R. China
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  • De-Pei Liu,

    1. State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
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  • Hongliang Li

    Corresponding author
    1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
    2. Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China
    • Address reprint requests to: Hongliang Li, M.D., Ph.D., Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, JieFang Road 238, Wuhan 430060, P.R. China. E-mail: lihl@whu.edu.cn; fax: +86-27-88076990; De-pei Liu, E-mail: liudp@pumc.edu.cn; and Xiao-dong Zhang, E-mail: zhangxd@whu.edu.cn.

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  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the key project of the National Natural Science foundation (81330005), the National Natural Science Foundation of China (81170086 and 81000342), the National Science and Technology Support Project (NO. 2011BAI15B02 and NO. 2012BAI39B05), the National Basic Research Program of China (2011CB503902) and the Special National Major Drug Discovery Program (2011ZX09307-302).

Abstract

Obesity and related metabolic diseases associated with chronic low-grade inflammation greatly compromise human health. Previous observations on the roles of interferon regulatory factors (IRFs) in the regulation of metabolism prompted investigation of the involvement of a key family member, IRF3, in metabolic disorders. IRF3 expression in the liver is decreased in animals with diet-induced and genetic obesity. The global knockout (KO) of IRF3 significantly promotes chronic high-fat diet (HFD)-induced hepatic insulin resistance and steatosis; in contrast, adenoviral-mediated hepatic IRF3 overexpression preserves glucose and lipid homeostasis. Furthermore, systemic and hepatic inflammation, which is increased in IRF3 KO mice, is attenuated by the overexpression of hepatic IRF3. Importantly, inhibitor of nuclear factor kappa B kinase beta subunit / nuclear factor kappa B (IKKβ/NF-κB) signaling is repressed by IRF3, and hepatic overexpression of the inhibitor of κB-α (IκBα) reverses HFD-induced insulin resistance and steatosis in IRF3 KO mice. Mechanistically, IRF3 interacts with the kinase domain of IKKβ in the cytoplasm and inhibits its downstream signaling. Moreover, deletion of the region of IRF3 responsible for the IRF3/IKKβ interaction inhibits the capacity of IRF3 to preserve glucose and lipid homeostasis. Conclusion: IRF3 interacts with IKKβ in the cytoplasm to inhibit IKKβ/NF-κB signaling, thus alleviating hepatic inflammation, insulin resistance, and hepatic steatosis. (Hepatology 2014;59:870–885)

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