Lipotoxicity of the pancreatic β-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids
Lipotoxicity of the pancreatic β-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids
复制标题
DOI：
10.2337/diabetes.50.2.315
复制
发表时间：
2001-02-01
期刊：
影响因子：
7.7
通讯作者：
Poitout, V
中科院分区：
文献类型：
--
作者：
Briaud, I;Harmon, JS;Poitout, V
在葡萄糖水平升高的情况下，分离的胰岛长时间暴露于超生理浓度的棕榈酸酯会降低胰岛素基因表达。本研究旨在确定这种现象是否与脂肪酸酯化成中性脂质的葡萄糖依赖性增加有关。在离体大鼠胰岛中检测了三种脂代谢关键酶--甘油三磷酸酰基转移酶（GPAT）、甘油二酯酰基转移酶（DGAT）和脂肪敏感脂肪酶（HSL）的基因表达。他们的表达水平没有受到影响后，72小时暴露于升高的葡萄糖和棕榈酸。为了确定葡萄糖对棕榈酸诱导的中性脂质合成的影响，将分离的大鼠胰岛在2.8或16.7 mmol/l葡萄糖下与痕量的[C-14]棕榈酸（含或不含0.5 mmol/l未标记棕榈酸）培养72 h。葡萄糖增加[C-14]棕榈酸酯掺入复合脂质。外源性棕榈酸酯的添加使脂质代谢向中性脂质合成方向发展。因此，中性脂质质量增加后，延长孵育与升高的棕榈酸只有在高葡萄糖的存在下。棕榈酸酯在高糖存在下增加中性脂质合成的能力在HIT细胞中是浓度依赖性的，并且与胰岛素mRNA水平呈负相关。2-溴棕榈酸酯，一种脂肪酸线粒体β-氧化的抑制剂，再现了棕榈酸酯对胰岛素mRNA水平的抑制作用。相反，棕榈酸甲酯，这是不代谢，和中链脂肪酸辛酸，这是容易氧化，不影响胰岛素基因表达，这表明脂肪酸抑制胰岛素基因表达需要激活的酯化途径。这些结果表明，胰岛素基因表达的抑制后，胰岛长期暴露于棕榈酸酯与葡萄糖依赖性增加的脂肪酸酯化成中性脂质。
Prolonged exposure of isolated islets to supraphysiologic concentrations of palmitate decreases insulin gene expression in the presence of elevated glucose levels. This study was designed to determine whether or not this phenomenon is associated with a glucose-dependent increase in esterification of fatty acids into neutral lipids. Gene expression of sn-glycerol-3-phosphate acyltransferase (GPAT), diacylglycerol acyltransferase (DGAT), and hormone-sensitive lipase (HSL), three key enzymes of lipid metabolism, was detected in isolated rat islets. Their levels of expression were not affected after a 72-h exposure to elevated glucose and palmitate. To determine the effects of glucose on palmitate-induced neutral lipid synthesis, isolated rat islets were cultured for 72 h with trace amounts of [C-14]palmitate with or without 0.5 mmol/l unlabeled palmitate, at 2.8 or 16.7 mmol/l glucose. Glucose increased incorporation of [C-14]palmitate into complex lipids. Addition of exogenous palmitate directed lipid metabolism toward neutral lipid synthesis. As a result, neutral lipid mass was increased upon prolonged incubation with elevated palmitate only in the presence of high glucose. The ability of palmitate to increase neutral lipid synthesis in the presence of high glucose was concentration-dependent in HIT cells and was inversely correlated to insulin mRNA levels. 2-Bromopalmitate, an inhibitor of fatty acid mitochondrial beta -oxidation, reproduced the inhibitory effect of palmitate on insulin mRNA levels. In contrast, palmitate methyl ester, which is not metabolized, and the medium-chain fatty acid octanoate, which is readily oxidized, did not affect insulin gene expression, suggesting that fatty-acid inhibition of insulin gene expression requires activation of the esterification pathway. These results demonstrate that inhibition of insulin gene expression upon prolonged exposure of islets to palmitate is associated with a glucose-dependent increase in esterification of fatty acids into neutral lipids.