Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 28, 2019; 25(36): 5451-5468
Published online Sep 28, 2019. doi: 10.3748/wjg.v25.i36.5451
Zinc-α2-glycoprotein 1 attenuates non-alcoholic fatty liver disease by negatively regulating tumour necrosis factor-α
Ting Liu, Xin Luo, Zheng-Hong Li, Jun-Cheng Wu, Sheng-Zheng Luo, Ming-Yi Xu
Ting Liu, Xin Luo, Zheng-Hong Li, Jun-Cheng Wu, Sheng-Zheng Luo, Ming-Yi Xu, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Ting Liu, Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Ting Liu, Xin Luo, Jun-Cheng Wu, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Author contributions: Xu MY designed the research; Liu T analyzed the data; Liu T and Luo X performed the research; Xu MY and Liu T wrote the paper; Wu JC, Li ZH, and Luo SZ developed software necessary to perform and record experiments.
Supported by the National Natural Science Foundation of China, No. 81570547 and No. 81770597; and the Development Program of China during the 13th Five-year Plan Period, No. 2017ZX10203202003005.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Shanghai General Hospital (2019KY034).
Institutional animal care and use committee statement: All animal experiments in this study were performed under guidelines approved by the Ethics Committee of Shanghai General Hospital (2019KY034).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest in this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ming-Yi Xu, PhD, MD, Professor of Medicine, Chief, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100, Haining Road, Shanghai 200080, China. xumingyi2014@163.com
Telephone: +86-21-63240090 Fax: +86-21-66283869
Received: June 19, 2019
Peer-review started: June 20, 2019
First decision: July 22, 2019
Revised: July 26, 2019
Accepted: August 24, 2019
Article in press: August 24, 2019
Published online: September 28, 2019
Processing time: 102 Days and 1.2 Hours
ARTICLE HIGHLIGHTS
Research background

Non-alcoholic fatty liver disease (NAFLD) is increasingly threatening people's health. Zinc-α2-glycoprotein 1 (AZGP1) was originally considered as a potential tumor marker, but subsequent studies have shown that it is also expressed in the liver, heart, lungs, and prostate. AZGP1 plays an important role in metabolism-related diseases, but the specific pathogenesis and therapeutic effects of AZGP1 in NAFLD remain uncertain.

Research motivation

Our findings will provide a basis for the application of AZGP1 in the therapy of NAFLD.

Research objectives

To examine the expression of AZGP1 in NAFLD patients, CCl4-treated mice fed a high fat diet (HFD), and human LO2 cells, and explore biological functions and potential mechanisms of AZGP1 in NAFLD.

Research methods

We detected the expression of AZGP1 in the liver tissues of NAFLD patients and CCl4-treated mice fed an HFD and human LO2 cells by qPCR and Western blot. The effects of AZGP1 on hepatocytes in vitro and in vivo were then assessed by overexpression and knockdown of AZGP1 in human LO2 cells and in an NAFLD mouse model. In further molecular mechanism research, LO2 cells were treated with sh-AZGP1 or combination of sh-AZGP1 and sh-TNF-α, OV-AZGP1 or combination of OV-AZGP1, and OV-TNF-α to investigate the specific effects of AZGP1 in vitro.

Research results

In the current study, we found that AZGP1 was significantly decreased in liver tissues from both humans and mice. Loss of AZGP1 activated inflammation, enhanced steatogenesis, increased lipid transport and accumulation, decreased fatty acid β-oxidation, promoted proliferation, and inhibited apoptosis in human LO2 cells. Over-expression of AZGP1 played an opposite role. In addition, AZGP1 attenuated NAFLD by blocking TNF-α-mediated inflammation and intracellular lipid deposition, promoting proliferation, and inhibiting apoptosis in LO2 cells. Finally, treatment with OV-AZGP1 plasmid in NAFLD mice significantly ameliorated liver damage and eliminated liver fat.

Research conclusions

AZGP1 is down-regulated in NAFLD, which could inhibit inflammation, accelerate lipolysis, accelerate proliferation, and reduce apoptosis via suppressing TNF-α. AZGP1 exerts a protective role against NAFLD.

Research perspectives

This study provides new insight into the role of AZGP1 in relieving NAFLD by down-relating TNF-α. AZGP1 might be a potential therapeutic approach to prevent and treat NAFLD.