Guanabenz Sensitizes Pancreatic β Cells to Lipotoxic Endoplasmic Reticulum Stress and Apoptosis
| Autor: | Miriam Cnop, Laurence Ladrière, Lorella Marselli, Mariana Igoillo-Esteve, Piero Marchetti, Daniel Andrade Da Cunha, Miriam H Hernangomez, Baroj Abdulkarim |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Programmed cell death Cells Biologie générale Wistar Drug Resistance Apoptosis Biology 03 medical and health sciences Endocrinology Insulin-Secreting Cells Internal medicine medicine Animals Humans Rats Wistar Protein kinase A Antihypertensive Agents Cells Cultured Diabétologie Cultured Guanabenz Kinase Endoplasmic reticulum Biologie moléculaire Enseignement des sciences Endoplasmic Reticulum Stress Lipids Rats 3. Good health 030104 developmental biology Lipotoxicity Unfolded protein response Phosphorylation Biologie cellulaire Biologie medicine.drug |
| Zdroj: | Endocrinology Endocrinology, 158 (6 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2016-1773 |
| Popis: | Deficient as well as excessive/prolonged endoplasmic reticulum (ER) stress signaling can lead to pancreatic β cell failure and the development of diabetes. Saturated free fatty acids (FFAs) such as palmitate induce lipotoxic ER stress in pancreatic β cells. One of the main ER stress response pathways is under the control of the protein kinase R-like endoplasmic reticulum kinase (PERK), leading to phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α). The antihypertensive drug guanabenz has been shown to inhibit eIF2α dephosphorylation and protect cells from ER stress. Here we examined whether guanabenz protects pancreatic β cells from lipotoxicity. Guanabenz induced β cell dysfunction in vitro and in vivo in rodents and led to impaired glucose tolerance. The drug significantly potentiated FFA-induced cell death in clonal rat β cells and in rat and human islets. Guanabenz enhanced FFA-induced eIF2α phosphorylation and expression of the downstream proapoptotic gene C/EBP homologous protein (CHOP), which mediated the sensitization to lipotoxicity. Thus, guanabenz does not protect β cells from ER stress; instead, it potentiates lipotoxic ER stress through PERK/eIF2α/CHOP signaling. These data demonstrate the crucial importance of the tight regulation of eIF2α phosphorylation for the normal function and survival of pancreatic β cells. SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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