title: A20 Attenuates FFAs-induced Lipid Accumulation in Nonalcoholic Steatohepatitis.
abstract: A20 is a ubiquitin-editing enzyme that attenuates the activity of proximal signaling complexes at pro-inflammatory receptors. It has been well documented that A20 protein plays an important role in response to liver injury and hepatocytes apoptosis in pro-inflammatory pathways. However, there was little evidence showing that A20 protein was involving in fatty-acid homeostasis except the up-regulation of two fatty acid metabolism regulatory genes at mRNA level (PPARa and CPT1a) by adenovirus-mediated A20 protein overexpression. In this study we found that: 1) the expression level of A20 protein was significantly higher in the steatotic liver from MCD-fed mice than the controls; 2) Overexpression of A20 protein suppressed FFAs-stimulated triglyceride deposition in HepG2 cells while under expression of A20 protein increased FFAs-stimulated triglyceride deposition; 3) Overexpression of A20 protein in HepG2 cells upregulated genes that promote β-oxidation and decreased the mRNA levels of key lipogenic genes such as fatty acid synthase (FAS), indicating A20 function as anti-steatotic factor by the activation of mitochondrial β-oxidation and attenuation of de novo lipogenesis; 4) Nonalcoholic steatohepatitis (NASH) patients showed significantly higher A20 expression level in liver compared with control individuals. Our results demonstrated that A20 protein plays an important role in fatty-acid homeostasis in human as well as animals. In addition, our data suggested that the pathological function of A20 protein in hepatocyte from lipotoxicity to NASH is by the alleviation of triglyceride accumulation in hepatocytes. Elevated expression of A20 protein could be a potential therapeutic strategy for preventing the progression of nonalcoholic steatohepatitis.
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China; ; 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Luoyan
authors.initials: L
authors.lastname: Ai
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China; ; 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China; ; 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Wu
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China; ; 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China; ; 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China; ; 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Su
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China; ; 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Jiang
authors.affiliation: 2. Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.
authors.forename: Antao
authors.initials: A
authors.lastname: Xu
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China;
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.affiliation: 1. Department of Health Care Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shang hai, China;
authors.forename: Zhuping
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000328:Adult; D016207:Cytokines / Q000378:metabolism; D004798:Enzymes / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004798:Enzymes; D005230:Fatty Acids, Nonesterified; D018836:Inflammation Mediators; D016328:NF-kappa B
keywords: A20; FFAs; NF-κB; Nonalcoholic Steatohepatitis