title: Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis.
abstract: Environmental factors such as diets rich in saturated fats contribute to dysfunction and death of pancreatic β-cells in diabetes. Endoplasmic reticulum (ER) stress is elicited in β-cells by saturated fatty acids. Here we show that palmitate-induced β-cell apoptosis is mediated by the intrinsic mitochondrial pathway. By microarray analysis, we identified a palmitate-triggered ER stress gene expression signature and the induction of the BH3-only proteins death protein 5 (DP5) and p53-upregulated modulator of apoptosis (PUMA). Knockdown of either protein reduced cytochrome c release, caspase-3 activation, and apoptosis in rat and human β-cells. DP5 induction depends on inositol-requiring enzyme 1 (IRE1)-dependent c-Jun NH₂-terminal kinase and PKR-like ER kinase (PERK)-induced activating transcription factor (ATF3) binding to its promoter. PUMA expression is also PERK/ATF3-dependent, through tribbles 3 (TRB3)-regulated AKT inhibition and FoxO3a activation. DP5(-/-) mice are protected from high fat diet-induced loss of glucose tolerance and have twofold greater pancreatic β-cell mass. This study elucidates the crosstalk between lipotoxic ER stress and the mitochondrial pathway of apoptosis that causes β-cell death in diabetes.
authors: Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors: Daniel A
authors: DA
authors: Cunha
authors: Mariana
authors: M
authors: Igoillo-Esteve
authors: Esteban N
authors: EN
authors: Gurzov
authors: Carla M
authors: CM
authors: Germano
authors: Najib
authors: N
authors: Naamane
authors: Ihsane
authors: I
authors: Marhfour
authors: Makiko
authors: M
authors: Fukaya
authors: Jean-Marie
authors: JM
authors: Vanderwinden
authors: Conny
authors: C
authors: Gysemans
authors: Chantal
authors: C
authors: Mathieu
authors: Lorella
authors: L
authors: Marselli
authors: Piero
authors: P
authors: Marchetti
authors: Heather P
authors: HP
authors: Harding
authors: David
authors: D
authors: Ron
authors: Décio L
authors: DL
authors: Eizirik
authors: Miriam
authors: M
authors: Cnop
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D020869:Gene Expression Profiling; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D019308:Palmitic Acid / Q000009:adverse effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C484586:HRK protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019308:Palmitic Acid