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
Abstract
BACKGROUND

Zinc-α2-glycoprotein 1 (AZGP1) plays important roles in metabolism-related diseases. The underlying molecular mechanisms and therapeutic effects of AZGP1 remain unknown in non-alcoholic fatty liver disease (NAFLD).

AIM

To explore the effects and potential mechanism of AZGP1 on NAFLD in vivo and in vitro.

METHODS

The expression of AZGP1 and its effects on hepatocytes were examined in NAFLD patients, CCl4-treated mice fed a high fat diet (HFD), and human LO2 cells.

RESULTS

AZGP1 levels were significantly decreased in liver tissues of NAFLD patients and mice. AZGP1 knockdown was found to activate inflammation; enhance steatogenesis, including promoting lipogenesis [sterol regulatory element-binding protein (SREBP)-1c, liver X receptor (LXR), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl CoA desaturase 1 (SCD)-1], increasing lipid transport and accumulation [fatty acid transport protein (FATP), carnitine palmitoyl transferase (CPT)-1A, and adiponectin], and reducing fatty acid β-oxidation [farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)-α]; accelerate proliferation; and reverse apoptosis in LO2 cells. AZGP1 overexpression (OV-AZGP1) had the opposite effects. Furthermore, AZGP1 alleviated 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 dramatically improved liver injury and eliminated liver fat in NAFLD mice.

CONCLUSION

AZGP1 attenuates NAFLD with regard to ameliorating inflammation, accelerating lipolysis, promoting proliferation, and reducing apoptosis by negatively regulating TNF-α. AZGP1 is suggested to be a novel promising therapeutic target for NAFLD.

Keywords: Non-alcoholic fatty liver disease, Zinc-α2-glycoprotein 1, Tumour necrosis factor-α, Inflammation, Lipid metabolism

Core tip: The expression of zinc-α2-glycoprotein 1 (AZGP1) was significantly down-regulated in liver tissues of non-alcoholic fatty liver disease (NAFLD) patients and mice. In LO2 cells, AZGP1 had the effects of alleviating NAFLD by means of blocking tumour necrosis factor-α signalling mediated inflammation and intracellular lipid deposition, promoting proliferation, and inhibiting apoptosis. AZGP1 treatment could attenuate NAFLD to some extent in mice. Therefore, AZGP1 is suggested to be a novel promising therapeutic target for NAFLD.