Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse beta cells, LDs are prominent in human beta cells, however, the regulation of LD mobilization (lipolysis) in human beta cells remains unclear. We found that glucose increases lipolysis in non-diabetic human islets, but not in type 2 diabetic (T2D) islets, indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets (shATGL) increased triglycerides, and the number and size of LDs indicating that ATGL is the principal lipase in human beta cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS) and insulin secretion to IBMX and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL deficient INS1 cells and human pseudoislets showed reduced Stx1a, a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human beta cells and supports insulin secretion by stabilizing Stx1a. The dysregulated lipolysis may contribute to LD accumulation and beta cell dysfunction in T2D islets.

中文翻译：

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脂肪甘油三酯脂肪酶是人类 β 细胞中脂滴动员的关键脂肪酶，对于维持 β 细胞中 Syntaxin1a 水平至关重要


当脂质过度积累导致细胞功能障碍时，脂滴（LD）经常会增加。与小鼠β细胞不同，LD在人类β细胞中很突出，然而，人类β细胞中LD动员（脂肪分解）的调节仍不清楚。我们发现葡萄糖会增加非糖尿病人胰岛的脂肪分解，但不会增加 2 型糖尿病 (T2D) 胰岛的脂肪分解，表明 T2D 胰岛中的脂肪分解失调。沉默人伪胰岛 (shATGL) 中的脂肪甘油三酯脂肪酶 (ATGL) 会增加甘油三酯，并且 LD 的数量和大小表明 ATGL 是人 β 细胞中的主要脂肪酶。在 shATGL 伪胰岛中，与扰乱对照相比，双相葡萄糖刺激的胰岛素分泌 (GSIS) 以及胰岛素对 IBMX 和 KCl 的分泌均减少，而耗氧率没有改变。与人类胰岛一样，INS1 细胞在 ATGL 沉默后表现出可见的 LD、葡萄糖反应性脂肪分解和 GSIS 损伤。 ATGL 缺陷型 INS1 细胞和人类伪胰岛显示出 Stx1a 减少，Stx1a 是 SNARE 的关键成分。 Stx1a 的蛋白酶体降解可能是通过 ATGL 缺陷 INS1 细胞中棕榈酰化的减少而加速的。因此，ATGL 负责人 β 细胞中 LD 的动员，并通过稳定 Stx1a 支持胰岛素分泌。脂解失调可能导致 T2D 胰岛中 LD 积累和 β 细胞功能障碍。