Ruderman N B, Saha A K, Vavvas D, Witters L A
Diabetes Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University Medical Center, Boston, Massachusetts 02118, USA.
Am J Physiol. 1999 Jan;276(1):E1-E18. doi: 10.1152/ajpendo.1999.276.1.E1.
Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the beta-isoform of acetyl-CoA carboxylase (ACCbeta). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCbeta and a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCbeta phosphorylation. Increases in cytosolic citrate leading to an increase in the concentration of malonyl-CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation, in keeping with a diminished need for fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCbeta and inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-789, 1963) and to a mechanism by which glucose might autoregulate its own use. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic beta-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily the activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogenesis of insulin resistance in muscle. That it may contribute to abnormalities associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA.
丙二酰辅酶A是肉碱棕榈酰转移酶（CPT）I的变构抑制剂，CPT I是一种控制长链脂肪酰基辅酶A（LCFA-CoA）进入线粒体进行氧化的酶。在大鼠骨骼肌中，丙二酰辅酶A的形成受乙酰辅酶A羧化酶β亚型（ACCβ）活性变化的急性（数分钟内）调节。这至少可通过两种机制发生：一种涉及胞质柠檬酸，它是ACCβ的变构激活剂及其底物胞质乙酰辅酶A的前体；另一种涉及ACCβ磷酸化的变化。当肌肉受到胰岛素和葡萄糖刺激，或因去神经支配而失活时，胞质柠檬酸增加导致丙二酰辅酶A浓度升高，这与这些情况下脂肪酸氧化需求减少一致。相反，在运动期间，当肌肉细胞对脂肪酸氧化的需求增加时，ATP/AMP和/或磷酸肌酸与肌酸的比值降低会激活一种AMP激活的蛋白激酶（AMPK）亚型，该亚型会使ACCβ磷酸化，并抑制其基础活性以及柠檬酸对其的激活作用。胞质柠檬酸的核心作用将这种丙二酰辅酶A调节机制与Randle等人提出的葡萄糖-脂肪酸循环概念（P. J. Randle、P. B. Garland、C. N. Hales和E. A. Newsholme，《柳叶刀》1: 785 - 789，1963年）以及葡萄糖可能自我调节其自身利用的机制联系起来。类似的柠檬酸介导的丙二酰辅酶A调节机制似乎也存在于其他组织中，包括胰腺β细胞、心脏，可能还有中枢神经系统。我们的假设是，通过改变LCFA-CoA和二酰甘油的胞质浓度，进而改变一种或多种蛋白激酶C亚型的活性，丙二酰辅酶A的变化在这些细胞的燃料代谢和信号转导之间提供了一种联系。我们还假设，如果丙二酰辅酶A调节机制失调导致丙二酰辅酶A和胞质LCFA-CoA浓度持续升高，可能在肌肉胰岛素抵抗的发病机制中起关键作用。也有人提出，它可能导致与其他组织胰岛素抵抗综合征相关的异常以及肥胖的发生。显然需要进行研究来检验这些假设，并探索运动和一些增加胰岛素敏感性的药物通过对丙二酰辅酶A和/或胞质LCFA-CoA的作用发挥作用的观点。
