Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, FREE FATTY-ACIDS, SELECTIVE-INHIBITION, JNK PHOSPHORYLATION, DEPENDENT APOPTOSIS, INDUCIBLE GENE, ER STRESS, KAPPA-B, PUMA, CONTRIBUTES, ACTIVATION, Aged, Animals, Apoptosis, Apoptosis Regulatory Proteins, Cell Line, Cells, Cultured, Endoplasmic Reticulum Stress, Gene Expression Profiling, Humans, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mitochondria, Palmitic Acid, Proto-Oncogene Proteins, RNA Interference, RNA, Messenger, RNA, Small Interfering, Rats, 11 Medical and Health Sciences, 32 Biomedical and clinical sciences

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 NH(2)-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.