Prevention of free fatty acid–induced hepatic lipotoxicity by 18β-glycyrrhetinic acid through lysosomal and mitochondrial pathways

Authors

  • Xudong Wu,

    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
    2. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA
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  • Luyong Zhang,

    Corresponding author
    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
    • China Pharmaceutical University, Nanjing, Jiangsu, 210009
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  • Emily Gurley,

    1. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA
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  • Elaine Studer,

    1. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA
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  • Jing Shang,

    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
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  • Tao Wang,

    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
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  • Cuifen Wang,

    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
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  • Ming Yan,

    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
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  • Zhenzhou Jiang,

    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
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  • Phillip B. Hylemon,

    1. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA
    2. Department of Internal Medicine/Gastrointestinal Division, Virginia Commonwealth University, Richmond, VA
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  • Arun J. Sanyal,

    1. Department of Internal Medicine/Gastrointestinal Division, Virginia Commonwealth University, Richmond, VA
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  • William M. Pandak Jr,

    1. Department of Internal Medicine/Gastrointestinal Division, Virginia Commonwealth University, Richmond, VA
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  • Huiping Zhou

    Corresponding author
    1. Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China
    2. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA
    3. Department of Internal Medicine/Gastrointestinal Division, Virginia Commonwealth University, Richmond, VA
    • Department of Microbiology & Immunology, Virginia Commonwealth University, P.O. Box 980678, Richmond, VA 23298-0678
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    • fax: 804-828-0676


  • Potential conflict of interest: Nothing to report.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and affects millions of people worldwide. Despite the increasing prevalence of NAFLD, the exact molecular/cellular mechanisms remain obscure and effective therapeutic strategies are still limited. It is well-accepted that free fatty acid (FFA)-induced lipotoxicity plays a pivotal role in the pathogenesis of NAFLD. Inhibition of FFA-associated hepatic toxicity represents a potential therapeutic strategy. Glycyrrhizin (GL), the major bioactive component of licorice root extract, has a variety of pharmacological properties including anti-inflammatory, antioxidant, and immune-modulating activities. GL has been used to treat hepatitis to reduce liver inflammation and hepatic injury; however, the mechanism underlying the antihepatic injury property of GL is still poorly understood. In this report, we provide evidence that 18 β-glycyrrhetinic acid (GA), the biologically active metabolite of GL, prevented FFA-induced lipid accumulation and cell apoptosis in in vitro HepG2 (human liver cell line) NAFLD models. GA also prevented high fat diet (HFD)-induced hepatic lipotoxicity and liver injury in in vivo rat NAFLD models. GA was found to stabilize lysosomal membranes, inhibit cathepsin B expression and enzyme activity, inhibit mitochondrial cytochrome c release, and reduce FFA-induced oxidative stress. These characteristics may represent major cellular mechanisms, which account for its protective effects on FFA/HFD-induced hepatic lipotoxicity. Conclusion: GA significantly reduced FFA/HFD-induced hepatic lipotoxicity by stabilizing the integrity of lysosomes and mitochondria and inhibiting cathepsin B expression and enzyme activity. (HEPATOLOGY 2008.)

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