Evidence for an anaplerotic malonyl-CoA pathway in pancreatic beta-cell nutrient signaling
Evidence for an anaplerotic malonyl-CoA pathway in pancreatic beta-cell nutrient signaling
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DOI：
10.2337/diabetes.45.2.190
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发表时间：
1996-02-01
期刊：
影响因子：
7.7
通讯作者：
Prentki, M
中科院分区：
文献类型：
--
作者：
Brun, T;Roche, E;Prentki, M
已经提出了燃料传感的代谢模型，其中丙二酰辅酶A和长链酰基辅酶A酯可能充当营养诱导的胰岛素释放中的耦合因子（Prentki M，Vischer S，Glennon MC，Regazzi R，Deeney J，Corkey BE：丙二酰辅酶A和长链酰基辅酶A酯作为营养诱导的胰岛素分泌中的代谢耦合因子。J Biol Chem 267：5802-5810，1992）。为了进一步了解胰岛组织中丙二酰辅酶A含量的控制，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）的短期和长期调节。这些酶催化丙二酰辅酶A的形成及其在脂肪酸从头生物发生中的用途。 ACC mRNA、蛋白质和酶活性在大鼠胰岛和克隆 β 细胞（HIT 细胞）中以明显水平存在。在胰岛素释放开始之前，向 HIT 细胞添加葡萄糖会导致 ACC 活性显着增加。禁食不会改变胰岛的 ACC 含量，但会显着下调脂肪生成组织的 ACC 含量。这表明 ACC 基因在脂肪生成组织和朗格汉斯岛中的差异调节。 FAS 在胰岛组织中表达很少，但 ACC 表达丰富。这表明β细胞中丙二酰辅酶A的主要功能是调节脂肪酸氧化，而不是充当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含量丰富，它可以通过柠檬酸盐补充丙二酰辅酶A生产所需的柠檬酸循环中间体。葡萄糖会导致β（HIT）细胞柠檬酸在分泌前升高，只有那些能够提高柠檬酸的营养素才能诱导有效的胰岛素释放。结果提供了支持该模型的新证据，并解释了为什么在葡萄糖刺激下，胰岛中的丙二酰辅酶A显着且快速地升高：1)葡萄糖升高柠檬酸，丙二酰辅酶A的前体； 2）葡萄糖增强ACC酶活性； 3) 丙二酰辅酶A不会转化为脂质。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 途径与胰岛素分泌有关的概念提供了证据。
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.