title: ER stress-mediated cell damage contributes to the release of EDA+fibronectin from hepatocytes in nonalcoholic fatty liver disease.
abstract: Fibronectin containing extra domain A (EDA+FN), a functional glycoprotein participating in several cellular processes, correlates with chronic liver disease. Herein, we aim to investigate the expression and secretion of EDA+FN from hepatocytes in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanisms. Circulating levels of EDA+FN were determined by ELISA in clinical samples. Western blotting and flow cytometry were performed on L02 and HepG2 cell lines to analyze whether the levels of EDA+FN were associated with endoplasmic reticulum (ER) stress-related cell death. Circulating levels of EDA+FN in NAFLD patients were significantly higher than those in control subjects, and positively related with severity of ultrasonographic steatosis score. In cultured hepatocytes, palmitate up-regulated the expression of EDA+FN in a dose-dependent manner. Conversely, when the cells were pretreated with 4-phenylbutyrate, a specific inhibitor of ER stress, up-regulation of EDA+FN could be abrogated. Moreover, silencing CHOP by shRNA enhanced the release of EDA+FN from hepatocytes following palmitate treatment, which was involved in ER stress-related cell damage. These findings suggest that the up-regulated level of EDA+FN is associated with liver damage in NAFLD, and ER stress-mediated cell damage contributes to the release of EDA+FN from hepatocytes.
authors.affiliation: Department of Blood Transfusion, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. 248961279@qq.com.
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.affiliation: School of Medicine, Jianghan University, Wuhan, 430000, China.
authors.forename: Fa-Hu
authors.initials: FH
authors.lastname: Yuan
authors.affiliation: School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, 430023, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, 430023, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, 430023, China. zhiguo_l@126.com.
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D000328:Adult; D016923:Cell Death; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C067625:FN1 protein, human; D005353:Fibronectins; D010168:Palmitates; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid
keywords: ER stress; fibronectin; necrosis; nonalcoholic fatty liver disease