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

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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.