Activation of the ATP-sensitive K+ channel by long chain acyl-CoA - A role in modulation of pancreatic beta-cell glucose sensitivity
Activation of the ATP-sensitive K+ channel by long chain acyl-CoA - A role in modulation of pancreatic beta-cell glucose sensitivity
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DOI：
10.1074/jbc.271.18.10623
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发表时间：
1996-05-03
影响因子：
4.8
通讯作者：
Corkey, BE
中科院分区：
文献类型：
--
作者：
Larsson, O;Deeney, JT;Corkey, BE
长期暴露于高水平的长链游离脂肪酸会减少葡萄糖诱导的胰岛和克隆性胰岛β细胞的胰岛素分泌。目前这种葡萄糖敏感性丧失的机制尚不清楚，在本研究中，我们评估了游离脂肪酸的代谢活性形式长链酰辅酶A酯(LC-CoA)增加可能介导葡萄糖敏感性丧失的可能性。我们观察到，与与白蛋白络合的0.5 mM棕榈酸孵育一夜，细胞内LC-CoA水平增加了100%以上，在同一研究中，总CoA池增加了约40%。膜片钳研究表明，饱和和不饱和的LC-CoA，而不是丙二酰辅酶A或游离Coash，可诱导ATP敏感的K+通道快速而缓慢地可逆开放，这种效应在10nn到1mM之间呈浓度依赖关系。这些结果表明，ATP调节的K+通道是LC-CoA的敏感靶点，提示高水平的LC-CoA可以防止通道关闭，并有助于β细胞葡萄糖不敏感的形成。
Long term exposure to elevated levels of long chain free fatty acids decreases glucose-induced insulin secretion from pancreatic islets and clonal pancreatic beta-cells. The mechanism for this loss of glucose sensitivity is at present not known, In this study, we evaluated the possibility that increases in long chain acyl-CoA esters (LC-CoA), the metabolically active form of free fatty acids, might mediate the loss of glucose sensitivity, We observed that cellular levels of LC-CoA increased more than 100% in response to overnight incubation with 0.5 mM palmitic acid complexed to albumin, In the same studies, the total CoA pool increased by about 40%. Patch-clamp studies demonstrated that saturated and unsaturated LC-CoA, but not malonyl-CoA or free CoASH, induced a rapid and slowly reversible opening of ATP-sensitive K+ channels, The effect was concentration-dependent between 10 nn and 1 mu M. These findings indicate that the ATP-regulated K+ channel is a sensitive target for LC-CoA and suggest that high levels of LC-CoA, which accumulate in response to hyperglycemia or prolonged exposure to free fatty acids, may prevent channel closure and contribute to the development of beta-cell glucose insensitivity.