Cholesterol biosynthesis pathway enhance regulated insulin secretion and secretory granule formation in pancreatic β-cells.

据报道，胆固醇在内分泌分泌颗粒（SG）膜中含量丰富。在这项研究中，我研究了胆固醇生物合成中间体和抑制剂在胰岛素分泌和SG形成机制中的作用。向细胞供应胆固醇有两种途径：一种是通过新生生物合成，另一种是通过LDL受体介导的内吞作用。我发现HMG-CoA抑制剂洛伐他汀可以减少胰岛素的分泌和含量，但不影响MIN6 β-细胞培养基中脂蛋白的消耗。胆固醇生物合成中间体甲羟戊酸、角鲨烯和香叶基焦磷酸（GGPP）增强了葡萄糖刺激胰岛素分泌（GSIS），前两者增加了胰岛素含量。在大鼠胰岛浸润实验中也证实了GGPP对gsis的增强作用。在形态学上，甲羟戊酸钠和角鲨烯增加了SGs种群，但不影响其大小。相反，洛伐他汀增加SG大小，减少胰岛素积聚的致密核，导致胰岛素含量下降。此外，胰岛素以组成方式分泌，表明受调节的胰岛素分泌受到破坏。

Cholesterol is reportedly abundant in the endocrine secretory granule (SG) membrane. In this study, I examined the involvement of cholesterol biosynthesis intermediates and inhibitors in insulin secretion and SG formation mechanisms. There are two routes for the supply of cholesterol to the cells: one via de novo biosynthesis, and the other via LDL receptor-mediated endocytosis. I found that insulin secretion and content are diminished by HMG-CoA inhibitor lovastatin, but not by lipoprotein depletion from the culture medium in MIN6 β-cells. Cholesterol biosynthesis intermediates, mevalonate, squalene, and geranylgeranyl pyrophosphate (GGPP) enhanced glucose-stimulated insulin secretion (GSIS), and the former two increased insulin content. The GSIS-enhancing effect of GGPP was also confirmed in perifusion with rat islets. Morphologically, mevalonate and squalene increased the population of SGs without affecting their size. In contrast, lovastatin increased the SG size with reduction of insulin-accumulating dense-cores, leading to a decrease in insulin content. Furthermore, insulin was secreted in a constitutive manner, indicating disruption of regulated insulin secretion.