Are the β-Cell Signaling Molecules Malonyl-CoA and Cystolic Long-Chain Acyl-CoA Implicated in Multiple Tissue Defects of Obesity and NIDDM?
Are the β-Cell Signaling Molecules Malonyl-CoA and Cystolic Long-Chain Acyl-CoA Implicated in Multiple Tissue Defects of Obesity and NIDDM?
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DOI：
10.2337/diab.45.3.273
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发表时间：
1996-03
期刊：
影响因子：
7.7
通讯作者：
M. Prentki;B. Corkey
中科院分区：
文献类型：
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作者：
M. Prentki;B. Corkey
广泛接受的肥胖相关NIDDM发病机制的理论已经暗示了明显不相容的事件，如精液：1）肌肉中的胰岛素抵抗，2）胰岛素分泌异常，和3）腹内脂肪增加。改变的循环或组织脂质是肥胖和NIDDM的特征性特征。这些缺陷的病因尚不清楚。从这个角度来看，我们提出，相同的代谢事件，升高的丙二酰辅酶A和长链酰基辅酶A（LC-CoA），在不同的组织介导，部分，多效性的改变特征的肥胖症和NIDDM。我们回顾了支持新概念的证据，即丙二酰辅酶A和LC-CoA在β细胞信号转导中作为代谢偶联因子，将燃料代谢与胰岛素分泌联系起来。我们认为，乙酰辅酶A羧化酶，合成丙二酰辅酶A，一个“丰富的信号，”和肉毒碱棕榈酰转移酶1，这是由它调节，可能会执行燃料传感器在β细胞，整合所有循环燃料刺激的浓度在β细胞以及肌肉，肝脏和脂肪组织。LC-CoA的靶效应物可能包括蛋白激酶C亚型、复合脂质形成、编码代谢酶或转导因子的基因以及蛋白酰化。我们支持这样的概念，即只有在葡萄糖和脂质都很丰富的条件下，代谢异常，这可能被称为糖脂氧症，变得明显。如果我们的假设是正确的，即丙二酰辅酶A和LC-CoA代谢中的常见信号异常有助于改变胰岛素释放和敏感性，那么它为不同遗传背景的个体中存在这些缺陷的可变组合以及难以确定其中一个或另一个是主要事件的事实提供了新的解释。
Widely held theories of the pathogenesis of obesity-associated NIDDM have implicated apparently incompatible events as seminal: 1) insulin resistance in muscle, 2) abnormal secretion of insulin, and 3) increases in intra-abdominal fat. Altered circulating or tissue lipids are characteristic features of obesity and NIDDM. The etiology of these defectss is not known. In this perspective, we propose that the same metabolic events, elevated malonyl-CoA and long-chain acyl-CoA (LC-CoA), in various tissues mediate, in part, the pleiotropic alterations characteristic of obesity and NIDDM. We review the evidence in support of the emerging concept that malonyl-CoA and LC-CoA act as metabolic coupling factors in β-cell signal transduction, linking fuel metabolism to insulin secretion. We suggest that acetyl-CoA carboxylase, which synthesizes malonyl-CoA, a “signal of plenty,” and carnitine palmitoyl transferase 1, which is regulated by it, may perform as fuel sensors in the β-cell, integrating the concentrations of all circulating fuel stimuli in the β-cell as well as in muscle, liver, and adipose tissue. The target effectors of LC-CoA may include protein kinase C sub-types, complex lipid formation, genes encoding metabolic enzymes or transduction factors, and protein acylation. We support the concept that only under conditions in which both glucose and lipids are plentiful will the metabolic abnormality, which may be termed glucolipoxia, become apparent. If our hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC-CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds and for the fact that it has been difficult to determine whether one or the other is the primary event.