Mitochondrial dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury

Authors

  • Mingyan Zhou,

    1. Department of Pharmacology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    2. Genome Research Center, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    3. Research Center of Heart, Brain, Hormone, and Healthy Aging, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
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  • Aimin Xu,

    1. Department of Pharmacology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    2. Research Center of Heart, Brain, Hormone, and Healthy Aging, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    3. Department of Medicine, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
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  • Paul K. H. Tam,

    1. Department of Surgery, Li Ka Shing Faculty of Medicine, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
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  • Karen S. L. Lam,

    1. Research Center of Heart, Brain, Hormone, and Healthy Aging, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    2. Department of Medicine, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
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  • Lawrence Chan,

    1. Division of Diabetes, Endocrinology, and Metabolism, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
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  • Ruby L. C. Hoo,

    1. Research Center of Heart, Brain, Hormone, and Healthy Aging, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    2. Department of Medicine, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
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  • Jing Liu,

    1. Department of Pharmacology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    2. Genome Research Center, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    3. Research Center of Heart, Brain, Hormone, and Healthy Aging, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
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  • Kim H. M. Chow,

    1. Department of Pharmacology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    2. Genome Research Center, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    3. Research Center of Heart, Brain, Hormone, and Healthy Aging, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
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  • Yu Wang

    Corresponding author
    1. Department of Pharmacology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    2. Genome Research Center, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    3. Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, Hong Kong, China
    • Department of Pharmacology and Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China
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    • fax: 852 28170859.


  • Potential conflict of interest: Nothing to report.

Abstract

Adiponectin is an adipocyte-derived hormone with a wide range of beneficial effects on obesity-related medical complications. Numerous epidemiological investigations in diverse ethnic groups have identified a lower adiponectin level as an independent risk factor for nonalcoholic fatty liver diseases and liver dysfunctions. Animal studies have demonstrated that replenishment of adiponectin protects against various forms of hepatic injuries, suggesting it to be a potential drug candidate for the treatment of liver diseases. This study was designed to investigate the cellular and molecular mechanisms underlying the hepatoprotective effects of adiponectin. Our results demonstrated that in adiponectin knockout (ADN-KO) mice, there was a preexisting condition of hepatic steatosis and mitochondrial dysfunction that might contribute to the increased vulnerabilities of these mice to secondary liver injuries induced by obesity and other conditions. Adenovirus-mediated replenishment of adiponectin depleted lipid accumulation, restored the oxidative activities of mitochondrial respiratory chain (MRC) complexes, and prevented the accumulation of lipid peroxidation products in ADN-KO mice but had no obvious effects on mitochondrial biogenesis. The gene and protein levels of uncoupling protein 2 (UCP2), a mitochondrial membrane transporter, were decreased in ADN-KO mice and could be significantly up-regulated by adiponectin treatment. Moreover, the effects of adiponectin on mitochondrial activities and on protection against endotoxin-induced liver injuries were significantly attenuated in UCP2 knockout mice. Conclusion: These results suggest that the hepatoprotective properties of adiponectin are mediated at least in part by an enhancement of the activities of MRC complexes through a mechanism involving UCP2. (HEPATOLOGY 2008.)

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