title: Endoplasmic reticulum oxidoreductin-1-like β (ERO1lβ) regulates susceptibility to endoplasmic reticulum stress and is induced by insulin flux in β-cells.
abstract: Hyperglycemia increases insulin flux through the endoplasmic reticulum (ER) of pancreatic β-cells, and the unfolded protein response pathway is required to enhance insulin processing. Pancreatic and duodenal homeobox 1 (PDX1), a key pancreatic transcription factor, regulates insulin along with targets involved in insulin processing and secretion. Here we find that PDX1 is a direct transcriptional regulator of ER oxidoreductin-1-like β (Ero1lβ), which maintains the oxidative environment of the ER to facilitate disulfide bond formation. PDX1 deficiency reduced Ero1lβ transcript levels in mouse islets and mouse insulinoma (MIN6) cells; moreover, PDX1 occupied the Ero1lβ promoter in β-cells. ERO1lβ levels were induced by high glucose concentrations and by the reducing agent dithiothreitol, indicating potential roles in adaptation to increased oxidative protein folding load in the β-cell ER. In MIN6 cells, small interfering RNA-mediated silencing of Ero1lβ decreased insulin content and increased susceptibility to ER stress-induced apoptosis. These findings demonstrate roles for the PDX1 target ERO1lβ in maintaining insulin content and regulating cell survival during ER stress.
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism and Department of Medicine, University of Pennsylvania School of Medicine, Clinical Research Building 726, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Khoo
authors.forename: Juxiang
authors.initials: J
authors.lastname: Yang
authors.forename: Gautam
authors.initials: G
authors.lastname: Rajpal
authors.forename: You
authors.initials: Y
authors.lastname: Wang
authors.forename: Jiangying
authors.initials: J
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D020868:Gene Silencing; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D019163:Reducing Agents / Q000633:toxicity; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; D019163:Reducing Agents; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C491864:Ero1l protein, mouse; D010088:Oxidoreductases