title: Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis.
abstract: Although the potential pathogenesis of nonalcoholic fatty liver disease (NAFLD) is unclear, increasing evidence indicates that endoplasmic reticulum (ER) stress may link free fatty acids to NAFLD. Since we previously reported that hepatic stimulator substance (HSS) could protect the liver from steatosis, this study is aimed to investigate whether HSS protection could be related with its inhibition on ER stress. The HSS gene was stably transfected into BEL-7402 hepatoma cells and effectively expressed in ER. The palmitic acid (PA)-induced heptocyte lipotoxicity was reproduced in the HSS-transfected cells, and HSS alleviation of the ER stress and apoptosis were subsequently examined. The results showed that PA treatment led to a heavy accumulation of fatty acids within the cells and a remarkable increase in reactive oxygen species (ROS). However, in the HSS-expressing cells, production of ROS was inhibited and ER stress-related marker glucose-regulated protein 78 (GRP-78), sterol regulatory element-binding protein (SREBP), anti-phospho-PRK-1ike ER kinase (p-PERK), anti-phospho-eukaryotic initiation factor 2α (p-eIF2α), and anti-C/EBP homologous protein (CHOP) were downregulated compared with the wild-type or mutant HSS-transfected cells. Furthermore, PA treatment severely impaired the activity of sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), leading to imbalanced calcium homeostasis during ER stress, which could be rescued in the HSS-trasfected cells. The protection provided by HSS to the SERCA is identical to that observed with N-acetyl-l-cysteine (NAC) and sodium dimercaptopropane sulfonate (Na-DMPS), which are two typical free radical scavengers. As a consequence, the rate of ER stress-mediated apoptosis in the HSS-expressing cells was significantly reduced. In conclusion, the protective effect of HSS against ER stress may be associated with the removal of ROS to restore the activity of the SERCA.
authors.affiliation: Department of Cell Biology and Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Shujun
authors.initials: S
authors.lastname: Jiang
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: An
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000096:biosynthesis; D051742:Transcription Factor CHOP; D014162:Transfection; D019892:eIF-2 Kinase / Q000096:biosynthesis
chemical_list: D000111:Acetylcysteine; D002118:Calcium; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D005230:Fatty Acids, Nonesterified; D006360:Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D017382:Reactive Oxygen Species; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D051779:Sterol Regulatory Element Binding Proteins; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C073456:hepatic stimulator substance
keywords: ER stress; SERCA; augmenter of liver regeneration; hepatic stimulator substance; nonalcoholic fatty liver disease