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抑制胆固醇生物合成损害了胰岛素分泌和胰岛B细胞电压门控钙通道功能

Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic β-cells
Xia F., Xie L., Mihic A., Gao X., Chen Y., Gaisano H.Y., Tsushima R.G.   |   2009/5/29 18:38:57 
Endocrinology, 2008   |   Volume 149, Issue 10  |   打印| 推荐给好友
上一篇: 格列本脲通过钙依赖的mTOR、PKA和 MEK途径激活大鼠胰岛B细胞基因转译
下一篇: 蛋白激酶C(PKCα和PKCe)对人内皮细胞Nox4基因表达的不同作用
Insulin secretion from pancreatic β-cells is mediated by the opening of voltage-gated Ca2+ channels (CaV) and exocytosis of insulin dense core vesicles facilitated by the secretory soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein machinery. We previously observed that β-cell exocytosis is sensitive to the acute removal of membrane cholesterol. However, less is known about the chronic changes in endogenous cholesterol and its biosynthesis in regulating β-cell stimulus-secretion coupling. We examined the effects of inhibiting endogenous β-cell cholesterol biosynthesis by using the squalene epoxidase inhibitor, NB598. The expression of squalene epoxidase in primary and clonal β-cells was confirmed by RT-PCR. Cholesterol reduction of 36-52% was observed in MIN6 cells, mouse and human pancreatic islets after a 48-h incubation with 10 μM NB598. A similar reduction in cholesterol was observed in the subcellular compartments of MIN6 cells. We found NB598 significantly inhibited both basal and glucose-stimulated insulin secretion from mouse pancreatic islets. Ca V channels were markedly inhibited by NB598. Rapid photolytic release of intracellular caged Ca2+ and simultaneous measurements of the changes in membrane capacitance revealed that NB598 also inhibited exocytosis independently from CaV channels. These effects were reversed by cholesterol repletion. Our results indicate that endogenous cholesterol in pancreatic β-cells plays a critical role in regulating insulin secretion. Moreover, chronic inhibition of cholesterol biosynthesis regulates the functional activity of CaV channels and insulin secretory granule mobilization and membrane fusion. Dysregulation of cellular cholesterol may cause impairment of β-cell function, a possible pathogenesis leading to the development of type 2 diabetes. Copyright © 2008 by The Endocrine Society.
Correspondence Address: Tsushima, R. G.; Department of Biology, York University, Toronto, ON M3J 1P3, Canada; email: tsushima@yorku.ca 
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