title: Role of ERp46 in β-cell lipoapoptosis through endoplasmic reticulum stress pathway as well as the protective effect of exendin-4.
abstract: Endoplasmic reticulum (ER) stress is considered as a key factor in free fatty acid (FFA)-induced apoptosis. ERp46, a new member of the thioredoxin family, is highly expressed in pancreatic β-cells and plays an important role in glucose toxicity. In this study we examined the potential role of ERp46 in palmitic acid (PA)-induced cell apoptosis and the protective role of exendin-4, a long-acting agonist of the hormone glucagon-like peptide-1 (GLP-1) receptor. The glucose-sensitive mouse β-pancreatic cell line, βTC6, was used to investigate the mechanisms of PA-induced apoptosis. Our results showed that ERp46 expression was reduced in a dose- and time-dependent manner after PA treatment. Furthermore, inhibition of ERp46 expression by small interfering (si)RNA-mediated silencing enhanced the ER stress response via three separate pathways and increased βTC6 cell apoptosis rates. Moreover, exendin-4 reduced the ER stress response and levels of apoptosis in NC transfected cells after PA treatment, but not in cells transfected with ERp46siRNA. In conclusion, ERp46 plays a protective role in PA-induced cell apoptosis by decreasing the ER stress response and might be a novel target for anti-diabetic drugs. Exendin-4 might protect against βTC6 cell lipoapoptosis in part by activating ERp46 signaling pathway.
authors.affiliation: Department of Endocrinology, The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350005, China.
authors.forename: Dan-Ling
authors.initials: DL
authors.lastname: Chen
authors.forename: Jing-Nan
authors.initials: JN
authors.lastname: Xiang
authors.forename: Li-Yong
authors.initials: LY
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019610:Cytoprotection; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D019308:Palmitic Acid / Q000009:adverse effects*; D010455:Peptides / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D018027:Receptors, Glucagon / Q000819:agonists; D013879:Thioredoxins / Q000235:genetics / Q000502:physiology*; D014688:Venoms / Q000494:pharmacology*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C482592:PC-TRP protein, mouse; D010455:Peptides; D034741:RNA, Small Interfering; D018027:Receptors, Glucagon; D014688:Venoms; D019308:Palmitic Acid; D013879:Thioredoxins; D000077270:Exenatide