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形成机制的参与。有两种途径向细胞供应胆固醇：一种是通过从头生物合成，另一种是通过LDL受体介导的内吞作用。我发现胰岛素分泌和含量被HMG-CoA抑制剂洛伐他汀减少，但不被MIN 6 β细胞培养基中的脂蛋白消耗所减少。胆固醇生物合成中间产物甲羟戊酸、角鲨烯和香叶基香叶基焦磷酸（GGPP）增强葡萄糖刺激的胰岛素分泌（GSIS），前两者增加胰岛素含量。GGPP的GSIS增强作用也在大鼠胰岛灌流中得到证实。在形态学上，甲羟戊酸和角鲨烯增加了SGs的数量，而不影响它们的大小。与此相反，洛伐他汀增加了SG的大小，减少胰岛素积累的致密核心，导致胰岛素含量下降。此外，胰岛素以组成性方式分泌，表明调节的胰岛素分泌被破坏。

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.