Cohen Guy, Shamni Ofer, Avrahami Yossef, Cohen Ofir, Broner Esther C, Filippov-Levy Natalie, Chatgilialoglu Chryssostomos, Ferreri Carla, Kaiser Nurit, Sasson Shlomo
Department of Pharmacology, Institute for Drug Research, Faculty of Medicine, The Hebrew University, Jerusalem, 9112102, Israel.
Diabetologia. 2015 Jun;58(6):1333-43. doi: 10.1007/s00125-015-3566-z. Epub 2015 Mar 26.
AIMS/HYPOTHESIS: Membrane phospholipids are the major intracellular source for fatty acid-derived mediators, which regulate myriad cell functions. We showed previously that high glucose levels triggered the hydrolysis of polyunsaturated fatty acids from beta cell phospholipids. These fatty acids were subjected to free radical-catalysed peroxidation to generate the bioactive aldehyde 4-hydroxy-2E-nonenal (4-HNE). The latter activated the nuclear peroxisome proliferator-activated receptor-δ (PPARδ), which in turn augmented glucose-stimulated insulin secretion. The present study aimed at investigating the combined effects of glucose and fatty acid overload on phospholipid turnover and the subsequent generation of lipid mediators, which affect insulin secretion and beta cell viability.
INS-1E cells were incubated with increasing glucose concentrations (5-25 mmol/l) without or with palmitic acid (PA; 50-500 μmol/l) and taken for fatty acid-based lipidomic analysis and functional assays. Rat isolated islets of Langerhans were used similarly.
PA was incorporated into membrane phospholipids in a concentration- and time-dependent manner; incorporation was highest at 25 mmol/l glucose. This was coupled to a rapid exchange with saturated, mono-unsaturated and polyunsaturated fatty acids. Importantly, released arachidonic acid and linoleic acid were subjected to peroxidation, resulting in the generation of 4-HNE, which further augmented insulin secretion by activating PPARδ in beta cells. However, this adaptive increase in insulin secretion was abolished at high glucose and PA levels, which induced endoplasmic reticulum stress, apoptosis and cell death.
CONCLUSIONS/INTERPRETATION: These findings highlight a key role for phospholipid remodelling and fatty acid peroxidation in mediating adaptive and cytotoxic interactions induced by nutrient overload in beta cells.
目的/假设：膜磷脂是脂肪酸衍生介质的主要细胞内来源，这些介质调节多种细胞功能。我们之前表明，高葡萄糖水平会引发β细胞磷脂中多不饱和脂肪酸的水解。这些脂肪酸会发生自由基催化的过氧化反应，生成生物活性醛4-羟基-2E-壬烯醛（4-HNE）。后者激活核过氧化物酶体增殖物激活受体δ（PPARδ），进而增强葡萄糖刺激的胰岛素分泌。本研究旨在探讨葡萄糖和脂肪酸过载对磷脂周转以及随后影响胰岛素分泌和β细胞活力的脂质介质生成的联合作用。
将INS-1E细胞与不同浓度（5 - 25 mmol/L）的葡萄糖孵育，有无棕榈酸（PA；50 - 500 μmol/L），然后进行基于脂肪酸的脂质组学分析和功能测定。同样使用大鼠分离的胰岛。
PA以浓度和时间依赖性方式掺入膜磷脂中；在25 mmol/L葡萄糖时掺入量最高。这与饱和、单不饱和和多不饱和脂肪酸的快速交换相关。重要的是，释放的花生四烯酸和亚油酸发生过氧化反应，生成4-HNE，其通过激活β细胞中的PPARδ进一步增强胰岛素分泌。然而，在高葡萄糖和PA水平下，这种胰岛素分泌的适应性增加被消除，高葡萄糖和PA水平会诱导内质网应激、凋亡和细胞死亡。
结论/解读：这些发现突出了磷脂重塑和脂肪酸过氧化在介导β细胞中营养过载诱导的适应性和细胞毒性相互作用中的关键作用。
