Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation
Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation
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DOI：
10.2337/diabetes.50.8.1771
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发表时间：
2001-08-01
期刊：
影响因子：
7.7
通讯作者：
Pipeleers, DG
中科院分区：
文献类型：
--
作者：
Cnop, M;Hannaert, JC;Pipeleers, DG
在Zucker糖尿病肥胖大鼠中的研究已经产生了这样的概念，即由于神经酰胺的形成，慢性升高的游离脂肪酸（FFA）水平可以引起载有磷脂酰胆碱的胰腺β细胞的凋亡，神经酰胺诱导一氧化氮（NO）依赖性细胞死亡。这种“脂毒性”假说可以解释肥胖者发生2型糖尿病的原因。本研究探讨是否长期暴露于游离脂肪酸影响存活的正常大鼠β细胞和是否与甘油三酯积累的发生结果。在5-100 nmol/l未结合的油酸酯和棕榈酸酯下检测到剂量依赖性细胞毒性，在48 h内发生坏死，在随后的6天培养期间发生额外的细胞凋亡。在等摩尔浓度下，棕榈酸酯的细胞毒性高于油酸酯，但低于其非代谢类似物溴棕榈酸酯。FFA细胞毒性没有抑制依托莫西（线粒体肉碱棕榈酰转移酶I的抑制剂）或抗氧化剂，它是不与诱导型NO合酶表达或NO形成。在第8天死亡的β细胞的百分比和第2天它们的细胞甘油三酯含量之间观察到负相关。对于等摩尔浓度的测试FFA，油酸引起的β细胞毒性最低，细胞质甘油三酯累积最高。另一方面，油酸酯在胰岛非β细胞中发挥最高毒性，其中未检测到FFA诱导的甘油三酯蓄积。在没有甘油三酯积累的条件下，较低的FFA浓度主要导致胰岛β细胞和非β细胞的细胞凋亡。结论：游离脂肪酸可通过一氧化氮非依赖性机制引起正常大鼠胰岛细胞死亡。正常β-细胞形成和积累细胞质甘油三酯的能力可能通过防止毒性游离脂肪酰基部分的细胞升高而充当针对FFA诱导的细胞凋亡的细胞保护机制。可以想象的是，这种潜力在体内可能发生的具有延长的甘油三酯积累的细胞中丧失或不足。
Studies in Zucker diabetic fatty rats have led to the concept that chronically elevated free fatty acid (FFA) levels can cause apoptosis of triglyceride-laden pancreatic beta -cells as a result of the formation of ceramides, which induce nitric oxide (NO)-dependent cell death. This "lipotoxicity" hypothesis could explain development of type 2 diabetes in obesity. The present study examines whether prolonged exposure to FFA affects survival of isolated normal rat beta -cells and whether the outcome is related to the occurrence of triglyceride accumulation. A dose-dependent cytotoxicity was detected at 5-100 nmol/l of unbound oleate and palmitate, with necrosis occurring within 48 h and an additional apoptosis during the subsequent 6 days of culture. At equimolar concentrations, the cytotoxicity of palmitate was higher than that of oleate but lower than that of its nonmetabolized analog bromopalmitate. FFA cytotoxicity was not suppressed by etomoxir (an inhibitor of mitochondrial carnitine palmitoyltransferase I) or by antioxidants; it was not associated with inducible NO synthase expression or NO formation. An inverse correlation was observed between the percentage of dead beta -cells on day 8 and their cellular triglyceride content on day 2. For equimolar concentrations of the tested FFA, oleate caused the lowest beta -cell toxicity and the highest cytoplasmic triglyceride accumulation. On the other hand, oleate exerted the highest toxicity in islet non-beta -cells, where no FFA-induced triglyceride accumulation was detected. In conditions without triglyceride accumulation, the lower FFA concentrations caused primarily apoptosis, both in islet beta -cells and non-beta -cells. It is concluded that FFAs can cause death of normal rat islet cells through an NO-independent mechanism. The ability of normal beta -cells to form and accumulate cytoplasmic triglycerides might serve as a cytoprotective mechanism against FFA-induced apoptosis by preventing a cellular rise in toxic free fatty acyl moieties. It is conceivable that this potential is lost or insufficient in cells with a prolonged triglyceride accumulation as may occur in vivo.