Institute for Medical Science, Ajou University School of Medicine, Wonchon-dong san 5, Yeongtong-gu, Suwon, Gyeonggi-do 442-749, Republic of Korea.
Endocrinology. 2011 Mar;152(3):816-27. doi: 10.1210/en.2010-0924. Epub 2011 Jan 5.
Saturated fatty acids are generally cytotoxic to β-cells. Accumulation of lipid intermediates and subsequent activation of lipid-mediated signals has been suggested to play a role in fatty acid-induced toxicity. To determine the effects of lipid metabolism in fatty acid-induced toxicity, lipid metabolism was modulated by up- and down-regulation of a lipogenic or fatty acid oxidation pathway, and the effects of various modulators on palmitate (PA)-induced INS-1 β-cell death were then evaluated. Treatment with the liver X receptor agonist T0901317 reduced PA-induced INS-1 cell death, regardless of its enhanced lipogenic activity. Furthermore, transient expression of a lipogenic transcription factor sterol regulatory element binding protein-1c (SREBP-1c) was also protective against PA-induced cytotoxicity. In contrast, knockdown of SREBP-1c or glycerol-3-phosphate acyltransferase 1 significantly augmented PA-induced cell death and reduced T0901317-induced protective effects. Conversely, T0901317 increased carnitine PA transferease-1 (CPT-1) expression and augmented PA oxidation. CPT-1 inhibitor etomoxir or CPT-1 knockdown augmented PA-induced cell death and reduced T0901317-induced protective effects, whereas the peroxisome proliferator-activated receptor (PPAR)-α agonist bezafibrate reduced PA-induced toxicity. In particular, T0901317 reduced the levels of PA-induced endoplasmic reticulum (ER) stress markers, including phospho-eukaryotic initiation factor-2α, phospho-C-Jun N terminal kinase, and CCAAT/enhancer-binding protein homologous protein. In contrast, knockdown of SREBP-1c or glycerol-3-phosphate acyltransferase 1 augmented PA-induced ER stress responses. Results of these experiments suggested that stimulation of lipid metabolism, including lipogenesis and fatty acid oxidation, protected β-cells from PA-induced lipotoxicity and that protection through enhanced lipogenesis was likely due to reduced ER stress.
饱和脂肪酸通常对β细胞具有细胞毒性。脂质中间产物的积累以及随后激活脂质介导的信号被认为在脂肪酸诱导的毒性中起作用。为了确定脂质代谢在脂肪酸诱导的毒性中的作用，通过上调和下调生脂或脂肪酸氧化途径来调节脂质代谢，然后评估各种调节剂对棕榈酸（PA）诱导的 INS-1β细胞死亡的影响。肝 X 受体激动剂 T0901317 的治疗减轻了 PA 诱导的 INS-1 细胞死亡，而不管其增强的生脂活性如何。此外，瞬时表达生脂转录因子固醇调节元件结合蛋白-1c（SREBP-1c）也可抵抗 PA 诱导的细胞毒性。相反，SREBP-1c 的敲低或甘油-3-磷酸酰基转移酶 1 显著增强了 PA 诱导的细胞死亡，并降低了 T0901317 诱导的保护作用。相反，T0901317 增加了肉毒碱 PA 转移酶-1（CPT-1）的表达并增强了 PA 氧化。CPT-1 抑制剂 etomoxir 或 CPT-1 敲低增强了 PA 诱导的细胞死亡并降低了 T0901317 诱导的保护作用，而过氧化物酶体增殖物激活受体（PPAR）-α激动剂 bezafibrate 降低了 PA 诱导的毒性。特别是，T0901317 降低了 PA 诱导的内质网（ER）应激标志物的水平，包括磷酸化真核起始因子-2α、磷酸化 c-Jun N 末端激酶和 CCAAT/增强子结合蛋白同源蛋白。相反，SREBP-1c 或甘油-3-磷酸酰基转移酶 1 的敲低增强了 PA 诱导的 ER 应激反应。这些实验的结果表明，刺激脂质代谢，包括生脂和脂肪酸氧化，可保护β细胞免受 PA 诱导的脂肪毒性，而通过增强生脂作用的保护可能是由于 ER 应激减少所致。
