Prentki M, Vischer S, Glennon M C, Regazzi R, Deeney J T, Corkey B E
Division de Biochimie Clinique, University of Geneva, Switzerland.
J Biol Chem. 1992 Mar 25;267(9):5802-10.
Several approaches were used to test the hypothesis proposing a role for acyl-CoA esters in nutrient-induced insulin release (Prentki, M., and Matschinsky, F. M. (1987) Physiol. Rev. 67, 1185-1248; Corkey, B. E., Glennon, M. C., Chen, K. S., Deeney, J. T., Matschinsky, F. M., and Prentki, M. (1989) J. Biol. Chem. 264, 21608-21612). Exogenous saturated long chain fatty acids markedly potentiated glucose-induced insulin release and elevated long chain acyl-CoA esters in the clonal beta-cell line (HIT). The secretory action depended on the fatty acid chain length, occurred in the range 3-20 microM (free concentration of palmitate), and was reversible and inhibitable by the neuromodulator somatostatin. 2-Bromopalmitate, an inhibitor of carnitine palmitoyl transferase I, suppressed the oxidation of endogenous fatty acids and promoted release of insulin. Only the nutrients or the combination of nutrients that caused secretion elevated malonyl-CoA. The short-chain acyl-CoA profile of HIT cells stimulated by various nutrients was determined in the presence of the nonstimulatory fuel glutamine. Glucose and leucine each provoked similar changes in acyl-CoA compounds. Both secretagogues elevated malonyl-CoA 3-6-fold, whereas succinyl-CoA, free CoASH, acetyl-CoA, and the free CoASH to acetyl-CoA ratio remained unaltered. Furthermore, only when inhibition of fatty acid oxidation was associated with a rise in malonyl-CoA did the total (mitochondrial plus cytoplasmic) content of long chain acyl-CoA esters correlate inversely with insulin release promoted by various nutrients. The results are consistent with the concept that fuel stimuli cause a rise in malonyl-CoA which by inhibiting fatty acid oxidation increase cytosolic long chain acyl-CoA esters. These data provide further support for a model in which malonyl-CoA and long chain acyl-CoAs esters serve as metabolic coupling factors when pancreatic beta-cells are stimulated with glucose and other nutrient secretagogues.
采用了几种方法来检验关于酰基辅酶A酯在营养物质诱导的胰岛素释放中起作用的假说（普伦蒂基，M.，和马奇辛斯基，F. M.（1987年）《生理学评论》67卷，1185 - 1248页；科尔基，B. E.，格伦农，M. C.，陈，K. S.，迪尼，J. T.，马奇辛斯基，F. M.，和普伦蒂基，M.（1989年）《生物化学杂志》264卷，21608 - 21612页）。外源性饱和长链脂肪酸显著增强了葡萄糖诱导的胰岛素释放，并提高了克隆β细胞系（HIT）中的长链酰基辅酶A酯水平。分泌作用取决于脂肪酸链长度，在3 - 20微摩尔（棕榈酸游离浓度）范围内发生，并且是可逆的，可被神经调质生长抑素抑制。肉碱棕榈酰转移酶I的抑制剂2 - 溴棕榈酸抑制了内源性脂肪酸的氧化并促进了胰岛素的释放。只有引起分泌的营养物质或营养物质组合才会使丙二酰辅酶A升高。在非刺激性燃料谷氨酰胺存在的情况下，测定了各种营养物质刺激的HIT细胞的短链酰基辅酶A谱。葡萄糖和亮氨酸各自引起酰基辅酶A化合物的类似变化。两种促分泌剂都使丙二酰辅酶A升高了3 - 6倍，而琥珀酰辅酶A、游离辅酶A、乙酰辅酶A以及游离辅酶A与乙酰辅酶A的比值保持不变。此外，只有当脂肪酸氧化的抑制与丙二酰辅酶A的升高相关时，长链酰基辅酶A酯的总（线粒体加细胞质）含量才与各种营养物质促进的胰岛素释放呈负相关。这些结果与以下概念一致，即燃料刺激导致丙二酰辅酶A升高，丙二酰辅酶A通过抑制脂肪酸氧化增加细胞质长链酰基辅酶A酯。这些数据为一个模型提供了进一步支持，在该模型中，当胰腺β细胞受到葡萄糖和其他营养促分泌剂刺激时，丙二酰辅酶A和长链酰基辅酶A酯作为代谢偶联因子。
