Faculties of Medical Sciences, University of Manchester, Oxford Road, Manchester, M13 9WL, UK.
Pharmacol Rep. 2013;65(5):1317-21. doi: 10.1016/s1734-1140(13)71490-7.
Saturated free fatty acids (FFAs) have a dual action on pancreatic β-cells, consisting of an initial enhancement and subsequent suppression of glucose-induced electrical activity and insulin release. These stimulatory and inhibitory effects have been attributed, at least in part, to the activation and inhibition, respectively, of the volume-regulated anion channel (VRAC) by FFAs. Both effects were independent of their metabolism. We have now investigated the effects of related aliphatic compounds in order to further define the determinants of FFA interaction with VRAC.
β-Cell VRAC and electrical activity were measured by conventional whole-cell and perforated patch recording, respectively. Cell volume was measured using a video-imaging technique.
In common with octanoic acid, addition of methyl octanoate or n-octanol resulted in a rapid, pronounced and reversible inhibition of VRAC activity. Addition of n-octane had no significant effect on VRAC activity. n-Octanol had a biphasic effect on β-cell membrane potential, namely a small transient depolarization followed by a marked hyperpolarization. n-Octanol was also found to prevent regulatory volume decrease in cells exposed to a hypotonic medium, consistent with VRAC inhibition.
It is suggested that methyl octanoate and n-octanol can mimic the effects of FFAs on the pancreatic β-cell via modulation of VRAC activity. The structural requirements for this effect appear to be a medium or long chain aliphatic compound containing at least one oxygen atom.
饱和游离脂肪酸（FFAs）对胰腺β细胞具有双重作用，包括对葡萄糖诱导的电活动和胰岛素释放的初始增强和随后的抑制。这些刺激和抑制作用至少部分归因于 FFAs 对体积调节阴离子通道（VRAC）的激活和抑制。这两种作用都与它们的代谢无关。我们现在研究了相关脂族化合物的作用，以进一步确定 FFAs 与 VRAC 相互作用的决定因素。
β细胞 VRAC 和电活动分别通过常规全细胞和穿孔贴片记录进行测量。细胞体积使用视频成像技术进行测量。
与辛酸相似，添加甲基辛酸或正辛醇会导致 VRAC 活性的快速、显著和可逆抑制。添加正辛烷对 VRAC 活性没有显著影响。正辛醇对β细胞膜电位具有双相作用，即小的短暂去极化，随后是明显的超极化。还发现正辛醇可防止暴露于低渗培养基中的细胞发生调节性体积减少，与 VRAC 抑制一致。
建议甲基辛酸和正辛醇可以通过调节 VRAC 活性模拟 FFAs 对胰腺β细胞的作用。这种作用的结构要求似乎是含有至少一个氧原子的中链或长链脂族化合物。
