title: Endoplasmic reticulum stress leads to lipid accumulation through upregulation of SREBP-1c in normal hepatic and hepatoma cells.
abstract: Endoplasmic reticulum stress (ERS) has been found in non-alcoholic fatty liver disease. The study was to further explore the mechanistic relationship between ERS and lipid accumulation. To induce ERS, the hepatoblastoma cell line HepG2 and the normal human L02 cell line were exposed to Tg for 48 h. RT-PCR and Western blot were performed to evaluate glucose-regulated protein (GRP-78) expression as a marker of ERS. ER ultrastructure was assessed by electron microscopy. Triglyceride content was examined by Oil Red O staining and quantitative intracellular triglyceride assay. The hepatic nuclear sterol regulatory element-binding protein (SREBP-1c), liver X receptor (LXRs), fatty acid synthase (FAS), and acetyl-coA carboxylase (ACC1) expressions were examined by real-time PCR and Western blot. 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) was used to inhibit S1P serine protease inhibitor, and SREBP-1c cleavage was evaluated under ERS. SREBP-1c was knockdown and its effect on lipid metabolism was observed. Tg treatment upregulated GRP-78 expression and severely damaged the ER structure in L02 and HepG2 cells. ERS increased triglyceride deposition and enhanced the expression of SREBP-1c, FAS, and ACC1, but have no influence on LXR. AEBSF pretreatment abolished Tg-induced SREBP-1c cleavage. Moreover, SREBP-1c silencing reduced triglycerides and downregulated FAS expression. Pharmacological ERS induced by Tg leads to lipid accumulation through upregulation of SREBP-1c in L02 and HepG2 cells.
authors.affiliation: Department of Gastroenterology and Hepatology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Dian-liang
authors.initials: DL
authors.lastname: Fang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Zhong-xin
authors.initials: ZX
authors.lastname: Sun
authors.forename: Hui-hong
authors.initials: HH
authors.lastname: Yu
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Wen-hui
authors.initials: WH
authors.lastname: Cheng
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Bo
authors.initials: B
authors.lastname: Ning
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D064429:Fatty Acid Synthases / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D013450:Sulfones; D014280:Triglycerides; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D019284:Thapsigargin; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase