title: PLIN2 is a Key Regulator of the Unfolded Protein Response and Endoplasmic Reticulum Stress Resolution in Pancreatic β Cells.
abstract: Progressive pancreatic β cell failure underlies the transition of impaired glucose tolerance to overt diabetes; endoplasmic reticulum (ER) stress expedites β cell failure in this situation. ER stress can be elicited by lipotoxicity and an increased demand for insulin in diabetes. We previously reported that the lipid droplet protein perilipin 2 (PLIN2) modulates lipid homeostasis in the liver. Here, we show that PLIN2 modulates the unfolded protein response (UPR) and ER stress in pancreatic β cells. PLIN2 expression goes up when β cells are exposed to a lipid load or to chemical ER stress inducers. Downregulation of PLIN2 ameliorates the effects of fatty acid- and chemical-induced ER stress, whereas PLIN2 overexpression exacerbates them. Diabetic Akita mice, which carry a heterozygous C96Y Ins2 mutation, exhibit elevated PLIN2 expression and ER stress in their β cells. Genetic ablation of Plin2 in Akita mice leads to mitigation of ER stress, forestalling β cell apoptosis, partially restoring β cell mass, and ameliorating diabetes. Mechanistic experiments showed that PLIN2 downregulation is associated with enhanced autophagic flux and accelerated ER stress resolution. In sum, we have identified a crucial role for PLIN2 in modulating autophagy, ER stress resolution, and β cell apoptosis and survival.
authors.affiliation: Department of Molecular &Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Diabetes, Endocrinology &Metabolism, Diabetes Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Tsung Huang
authors.initials: TH
authors.lastname: Tsai
authors.affiliation: Department of Medicine, Division of Diabetes, Endocrinology &Metabolism, Diabetes Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Molecular &Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Pradip
authors.initials: P
authors.lastname: Saha
authors.affiliation: Department of Molecular &Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|Department of Medicine, Division of Diabetes, Endocrinology &Metabolism, Diabetes Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Molecular &Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|Department of Medicine, Division of Diabetes, Endocrinology &Metabolism, Diabetes Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Benny Hung-Junn
authors.initials: BH
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002460:Cell Line; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D019301:Oleic Acid / Q000494:pharmacology; D000070780:Perilipin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D005230:Fatty Acids, Nonesterified; D000070780:Perilipin-2; D034741:RNA, Small Interfering; D014415:Tunicamycin; D019301:Oleic Acid