title: Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic beta-cells.
abstract: Chronic exposure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic beta-cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic beta-cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced beta-cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in beta-cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate.
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, 101 College Street, TMOT 10-707, Toronto, ON, Canada, M5G1L7.
authors.forename: Elida
authors.initials: E
authors.lastname: Lai
authors.forename: George
authors.initials: G
authors.lastname: Bikopoulos
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
authors.forename: Maria
authors.initials: M
authors.lastname: Rozakis-Adcock
authors.forename: Allen
authors.initials: A
authors.lastname: Volchuk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage*; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000648:ultrastructure*; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology; D019308:Palmitic Acid / Q000008:administration & dosage; D051381:Rats; D013230:Stearoyl-CoA Desaturase; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005230:Fatty Acids, Nonesterified; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D019308:Palmitic Acid; D019284:Thapsigargin; D013230:Stearoyl-CoA Desaturase