Brun T, Roche E, Assimacopoulos-Jeannet F, Corkey B E, Kim K H, Prentki M
Department of Nutrition, University of Montreal Medical School, Quebec, Canada.
Diabetes. 1996 Feb;45(2):190-8. doi: 10.2337/diab.45.2.190.
A metabolic model of fuel sensing has been proposed in which malonyl-CoA and long-chain acyl-CoA esters may act as coupling factors in nutrient-induced insulin release (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney J, Corkey BE: Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 267:5802-5810, 1992). To gain further insight into the control of malonyl-CoA content in islet tissue, we have studied the short- and long-term regulation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the beta-cell. These enzymes catalyze the formation of malonyl-CoA and its usage for de novo fatty acid biogenesis. ACC mRNA, protein, and enzymatic activity are present at appreciable levels in rat pancreatic islets and clonal beta-cells (HIT cells). Glucose addition to HIT cells results in a marked increase in ACC activity that precedes the initiation of insulin release. Fasting does not modify the ACC content of islets, whereas it markedly downregulates that of lipogenic tissues. This indicates differential regulation of the ACC gene in lipogenic tissues and the islets of Langerhans. FAS is very poorly expressed in islet tissue, yet ACC is abundant. This demonstrates that the primary function of malonyl-CoA in the beta-cells is to regulate fatty acid oxidation, not to serve as a substrate for fatty acid biosynthesis. The anaplerotic enzyme pyruvate carboxylase, which allows the replenishment of citric acid cycle intermediates needed for malonyl-CoA production via citrate, is abundant in islet tissue. Glucose causes an elevation in beta (HIT)-cell citrate that precedes secretion, and only those nutrients that can elevate citrate induce effective insulin release. The results provide new evidence in support of the model and explain why malonyl-CoA rises markedly and rapidly in islets upon glucose stimulation: 1) glucose elevates citrate, the precursor of malonyl-CoA; 2) glucose enhances ACC enzymatic activity; and 3) malonyl-CoA is not diverted to lipids. The data suggest that ACC is a key enzyme in metabolic signal transduction of the beta-cell and provide evidence for the concept that an anaplerotic/malonyl-CoA pathway is implicated in insulin secretion.
一种燃料感应的代谢模型已被提出，其中丙二酰辅酶A和长链酰基辅酶A酯可能作为营养诱导胰岛素释放的偶联因子（普伦蒂基M、维舍尔S、格伦农MC、雷加齐R、迪尼J、科尔基BE：丙二酰辅酶A和长链酰基辅酶A酯作为营养诱导胰岛素分泌的代谢偶联因子。《生物化学杂志》267:5802 - 5810，1992年）。为了进一步深入了解胰岛组织中丙二酰辅酶A含量的调控，我们研究了β细胞中乙酰辅酶A羧化酶（ACC）和脂肪酸合酶（FAS）的短期和长期调控。这些酶催化丙二酰辅酶A的形成及其用于从头合成脂肪酸。ACC mRNA、蛋白质和酶活性在大鼠胰岛和克隆β细胞（HIT细胞）中以可观的水平存在。向HIT细胞中添加葡萄糖会导致ACC活性显著增加，这发生在胰岛素释放开始之前。禁食不会改变胰岛中ACC的含量，而它会显著下调脂肪生成组织中的ACC含量。这表明脂肪生成组织和胰岛中ACC基因的调控存在差异。FAS在胰岛组织中表达极低，但ACC含量丰富。这表明丙二酰辅酶A在β细胞中的主要功能是调节脂肪酸氧化，而不是作为脂肪酸生物合成的底物。回补酶丙酮酸羧化酶在胰岛组织中丰富，它能通过柠檬酸补充丙二酰辅酶A生成所需的柠檬酸循环中间产物。葡萄糖会导致β（HIT）细胞中的柠檬酸在分泌前升高，并且只有那些能升高柠檬酸的营养物质才能诱导有效的胰岛素释放。这些结果为该模型提供了新的证据，并解释了为什么在葡萄糖刺激下胰岛中丙二酰辅酶A会显著且迅速升高：1）葡萄糖升高了丙二酰辅酶A的前体柠檬酸；2）葡萄糖增强了ACC酶活性；3）丙二酰辅酶A不会被用于合成脂质。数据表明ACC是β细胞代谢信号转导中的关键酶，并为回补/丙二酰辅酶A途径参与胰岛素分泌这一概念提供了证据。
