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Molecular Biology

Zinc alpha2 glycoprotein protects against obesity-induced hepatic steatosis

International Journal of Obesityvolume 42pages14181430 (2018) | Download Citation

Abstract

Background/Aim

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation.

Methods

ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes.

Results

ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes.

Conclusions

Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.

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Acknowledgments

This work was supported by research grants from the National Natural Science Foundation of China (81270925 and 81070667), Major Scientific Research Projects of Hunan Health and Family Planning Commission (A2017011).

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Author notes

  1. These authors contributed equally: Xin-Hua Xiao, Ya-Di Wang.

Affiliations

  1. Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China

    • Xin-Hua Xiao
    • , Ya-Di Wang
    • , Xiao-Yan Qi
    • , Yuan-Yuan Wang
    • , Jiao-Yang Li
    • , Han Li
    • , Pei-Ying Zhang
    • , Hai-Lin Liao
    • , Mei-Hua Li
    • , Zhe-Zhen Liao
    • , Jing Yang
    • , Ge-Bo Wen
    •  & Jiang-Hua Liu
  2. Department of Pathology & Immunology, Washington University in, St. Louis, MO, 63110, USA

    • Can-Xin Xu

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The authors declare that they have no conflict of interest.

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Correspondence to Jiang-Hua Liu.

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DOI

https://doi.org/10.1038/s41366-018-0151-9