Molecular or pharmacologic perturbation of the link between glucose and lipid metabolism is without effect on glucose-stimulated insulin secretion - A re-evaluation of the long-chain acyl-CoA hypothesis
Molecular or pharmacologic perturbation of the link between glucose and lipid metabolism is without effect on glucose-stimulated insulin secretion - A re-evaluation of the long-chain acyl-CoA hypothesis
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DOI：
10.1074/jbc.273.26.16146
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发表时间：
1998-06-26
影响因子：
4.8
通讯作者：
Newgard, CB
中科院分区：
文献类型：
--
作者：
Antinozzi, PA;Segall, L;Newgard, CB
葡萄糖刺激朗格汉斯胰岛分泌胰岛素的机制尚不完全清楚。研究表明，丙二酰辅酶A通过抑制脂肪酸氧化和促进胞质长链酰基辅酶A（LC-CoA）的积累发挥调节作用。在当前的研究中，我们通过使用分子和药理学方法在葡萄糖刺激期间扰乱INS-1胰岛素瘤细胞或大鼠胰岛的脂质代谢来重新评估这种“长链酰基辅酶A假说”。首先，我们构建了含有编码丙二酰辅酶A脱羧酶（AdCMV-MCD）的cDNA的重组腺病毒，该酶将丙二酰辅酶A脱羧为乙酰辅酶A。与 AdCMV-β Gal 处理的细胞相比，在 3 和 20 mM 葡萄糖条件下，用 AdCMV-MCD 处理的 INS-1 细胞显着降低了细胞内丙二酰辅酶 A 水平。此外，在 20 mM 葡萄糖下，AdCMV-MCD 处理的细胞在抑制 [1-C-14] 棕榈酸氧化方面效果较差，与 AdCMV-beta GAL 处理或未处理的 INS-1 细胞相比，细胞脂质中掺入的标记棕榈酸和标记葡萄糖分别减少 43% 和 50%。尽管 MCD 的表达引起了巨大的代谢变化，但相对于对照，响应葡萄糖的胰岛素分泌没有改变。另一种扰乱脂质代谢的药理学方法是使用三羟甲基纤维素 C 来抑制长链酰基辅酶 A 合成酶。该试剂可有效减弱棕榈酸酯氧化和葡萄糖或棕榈酸酯掺入细胞脂质，并导致总 LC-CoA 减少 47%。尽管如此，该药物对胰岛或 INS-1 细胞中葡萄糖刺激的胰岛素分泌没有影响。我们的结论是，葡萄糖和脂质代谢之间联系的显着破坏不会损害胰岛或 INS-1 细胞中葡萄糖刺激的胰岛素分泌。
The mechanism by which glucose stimulates insulin secretion from the pancreatic islets of Langerhans is incompletely understood. It has been suggested that malonyl-CoA plays a regulatory role by inhibiting fatty acid oxidation and promoting accumulation of cytosolic long-chain acyl-CoA (LC-CoA). In the current study, we have re evaluated this "long-chain acyl-CoA hypothesis" by using molecular and pharmacologic methods to perturb lipid metabolism in INS-1 insulinoma cells or rat islets during glucose stimulation. First, we constructed a recombinant adenovirus containing the cDNA encoding malonyl-CoA decarboxylase (AdCMV-MCD), an enzyme that decarboxylates malonyl-CoA to acetyl-CoA. INS-1 cells treated with AdCMV-MCD had dramatically lowered intracellular malonyl CoA levels compared with AdCMV-beta Gal-treated cells at both 3 and 20 mM glucose. Further, at 20 mM glucose, AdCMV-MCD-treated cells were less effective at suppressing [1-C-14]palmitate oxidation and incorporated 43% less labeled palmitate and 50% less labeled glucose into cellular lipids than either AdCMV-beta GAL-treated or untreated INS-1 cells. Despite the large metabolic changes caused by expression of MCD, insulin secretion in response to glucose was unaltered relative to controls. The alternative, pharmacologic approach for perturbing lipid metabolism was to use triacsin C to inhibit long-chain acyl-CoA synthetase. This agent caused potent attenuation of palmitate oxidation and glucose or palmitate incorporation into cellular lipids and also caused a 47% decrease in total LC-CoA. Despite this, the drug had no effect on glucose-stimulated insulin secretion in islets or INS-1 cells. We conclude that significant disruption of the link between glucose and lipid metabolism does not impair glucose-stimulated insulin secretion in pancreatic islets or INS-1 cells.