Caveolin-1 is essential for protecting against binge drinking-induced liver damage through inhibiting reactive nitrogen species

Authors

  • Lei Gao,

    1. School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
    2. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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  • Yingchun Zhou,

    1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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  • Weichao Zhong,

    1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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  • Xiaohua Zhao,

    1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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  • Chun Chen,

    1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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  • Xingmiao Chen,

    1. School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
    2. Research Center of Heart, Brain, Hormone & Healthy Aging, the University of Hong Kong, Hong Kong SAR, China
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  • Yong Gu,

    1. School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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  • Jianping Chen,

    1. School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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  • Zhiping Lv,

    Corresponding author
    1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
    • Address reprint request to: Jiangang Shen, M.D., Ph.D., School of Chinese Medicine, Research Center of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China 999077. E-mail: shenjg@hku.hk; fax: +852 28725476; or Zhiping Lv, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China. E-mail: lzp48241@126.com; fax: +020 61648244.

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    • These authors contributed equally to this work.

  • Jiangang Shen

    Corresponding author
    1. School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
    2. Research Center of Heart, Brain, Hormone & Healthy Aging, the University of Hong Kong, Hong Kong SAR, China
    • Address reprint request to: Jiangang Shen, M.D., Ph.D., School of Chinese Medicine, Research Center of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China 999077. E-mail: shenjg@hku.hk; fax: +852 28725476; or Zhiping Lv, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China. E-mail: lzp48241@126.com; fax: +020 61648244.

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    • These authors contributed equally to this work.


  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Seed Funding Program for Basic Research (no. 201111159021), the Seed Funding Program for Applied Research (no. 201109160022), The University of Hong Kong, and the General Research Fund, Hong Kong SAR (HKU 777611M).

Abstract

Caveolin-1 (Cav-1) is known to participate in many diseases, but its roles in alcoholic liver injury remain unknown. In the present study, we aimed to explore the roles of Cav-1 in protecting hepatocytes from ethanol-mediated nitrosative injury. We hypothesized that Cav-1 could attenuate ethanol-mediated nitrosative stress and liver damage through regulating epidermal growth factor receptor/signal transducer and activator of transcription 3/inducible nitric oxide synthase (EGFR/STAT3/iNOS)-signaling cascades. Ethanol-fed mice had time- and dose-dependent increases of Cav-1 in serum and liver with peak increase at 12 hours. Compared to wild-type mice, Cav-1 deficiency mice revealed higher expression of iNOS, higher levels of nitrate/nitrite and peroxynitrite, and had more serious liver damage, accompanied with higher levels of cleaved caspase-3 and apoptotic cell death in liver, and higher levels of alanine aminotransferase and aspartate aminotransferase in serum. Furthermore, the results revealed that the ethanol-mediated Cav-1 increase was in an extracellular signal-regulated kinase–dependent manner, and Cav-1 protected hepatocytes from ethanol-mediated apoptosis by inhibiting iNOS activity and regulating EGFR- and STAT3-signaling cascades. In agreement with these findings, clinical trials in human subjects revealed that serum Cav-1 level was time dependently elevated and peak concentration was observed 12 hours after binge drinking. Alcohol-induced liver lesions were negatively correlated with Cav-1 level, but positively correlated with nitrate/nitrite level, in serum of binge drinkers. Conclusions: Cav-1 could be a cellular defense protein against alcoholic hepatic injury through inhibiting reactive nitrogen species and regulating EGFR/STAT3/iNOS-signaling cascades. (Hepatology 2014;60:687–699)

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