Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats -: Role of serine palmitoyltransferase overexpression
Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats -: Role of serine palmitoyltransferase overexpression
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DOI：
10.1074/jbc.273.49.32487
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发表时间：
1998-12-04
影响因子：
4.8
通讯作者：
Unger, RH
中科院分区：
文献类型：
--
作者：
Shimabukuro, M;Higa, M;Unger, RH
我们报道，在肥胖 fa/fa Zucker 糖尿病脂肪 (ZDF) 大鼠的富含脂肪的胰岛中观察到的 β 细胞脂肪凋亡是由神经酰胺过量产生的结果，神经酰胺是细胞凋亡级联的引发剂，由长链脂肪酸 (FA) 诱导，而细胞因子诱导的细胞凋亡的神经酰胺可能源自 鞘磷脂水解、FA诱导的神经酰胺过量产生似乎源自FA。因此，我们对丝氨酸棕榈酰转移酶 (SPT) 的 mRNA 进行半定量，该酶催化神经酰胺合成的第一步。 fa/fa 胰岛中的该值比 +/+ 对照高 2-3 倍。在 fa/fa 胰岛中，由 [H-3] 丝氨酸形成的 [H-3] 神经酰胺高出 2.2-4.5 倍，Triacsin-C（可阻断棕榈酰辅酶 A 合成）和 L-环丝氨酸（可阻断 SPT 活性）完全阻断由 [H-3] 丝氨酸形成 [H-3] 神经酰胺。 fa/fa 大鼠的胰岛对瘦素的脂减少作用没有反应，瘦素通常会消耗脂肪并防止 FA 对 SPT 的上调。为了确定瘦素无反应在 SPT 过度表达中的作用，我们将野生型 OB-Rb cDNA 转移到它们的胰岛中；现在瘦素完全阻断了 FA 诱导的 SPT mRNA 的过度增加，同时降低了脂肪含量。用 L-环丝氨酸治疗糖尿病前期 ZDF 大鼠 2 周，可部分阻止体内 β 细胞脂肪凋亡。神经酰胺含量和 DNA 碎片均下降 40-50%。我们得出的结论是，ZDF 大鼠的脂肪细胞凋亡是由 FA 的神经酰胺合成增强介导的，而 SPT 抑制剂的阻断可防止脂肪细胞凋亡。
We reported that the lipoapoptosis of beta-cells observed in fat-laden islets of obese fa/fa Zucker Diabetic Fatty (ZDF) rats results from overproduction of ceramide, an initiator of the apoptotic cascade and is induced by long-chain fatty acids (FA), Whereas the ceramide of cytokine-induced apoptosis may be derived from sphingomyelin hydrolysis, FA-induced ceramide overproduction seems to be derived from FA. We therefore semiquantified mRNA of serine palmitoyltransferase (SPT), which catalyzes the first step in ceramide synthesis. It was 2-3-fold higher in fa/fa islets than in +/+ controls. [H-3]Ceramide formation from [H-3]serine was 2.2-4.5-fold higher in fa/fa islets, Triacsin-C, which blocks palmitoyl-CoA synthesis, and L-cycloserine, which blocks SPT activity, completely blocked [H-3]ceramide formation from [H-3]serine. Islets of fa/fa rats are unresponsive to the lipopenic action of leptin, which normally depletes fat and prevents FA up-regulation of SPT, To determine the role of leptin unresponsiveness in the SPT overexpression, we transferred wild type OB-Rb cDNA to their islets; now leptin completely blocked the exaggerated FA-induced increase of SPT mRNA while reducing the fat content. Beta-cell lipoapoptosis was partially prevented in vivo by treating prediabetic ZDF rats with L-cycloserine for 2 weeks. Ceramide content and DNA fragmentation both declined 40-50%. We conclude that lipoapoptosis of ZDF rats is mediated by enhanced ceramide synthesis from FA and that blockade by SPT inhibitors prevents lipoapoptosis.