Holness M J, Sugden M C
Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, Medical Sciences Building, Bart's and the London, Queen Mary's School of Medicine and Dentistry, University of London, Mile End Road, London E1 4NS, U.K.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1143-51. doi: 10.1042/bst0311143.
PDC (pyruvate dehydrogenase complex) catalyses the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle. Regulation of PDC determines and reflects substrate preference and is critical to the 'glucose-fatty acid cycle', a concept of reciprocal regulation of lipid and glucose oxidation to maintain glucose homoeostasis developed by Philip Randle. Mammalian PDC activity is inactivated by phosphorylation by the PDKs (pyruvate dehydrogenase kinases). PDK inhibition by pyruvate facilitates PDC activation, favouring glucose oxidation and malonyl-CoA formation: the latter suppresses LCFA (long-chain fatty acid) oxidation. PDK activation by the high mitochondrial acetyl-CoA/CoA and NADH/NAD(+) concentration ratios that reflect high rates of LCFA oxidation causes blockade of glucose oxidation. Complementing glucose homoeostasis in health, fuel allostasis, i.e. adaptation to maintain homoeostasis, is an essential component of the response to chronic changes in glycaemia and lipidaemia in insulin resistance. We develop the concept that the PDKs act as tissue homoeostats and suggest that long-term modulation of expression of individual PDKs, particularly PDK4, is an essential component of allostasis to maintain homoeostasis. We also describe the intracellular signals that govern the expression of the various PDK isoforms, including the roles of the peroxisome proliferator-activated receptors and lipids, as effectors within the context of allostasis.
丙酮酸脱氢酶复合体（PDC）催化丙酮酸的氧化脱羧反应，将糖酵解与三羧酸循环连接起来。PDC的调节决定并反映底物偏好，对“葡萄糖-脂肪酸循环”至关重要，这是菲利普·兰德尔提出的脂质和葡萄糖氧化相互调节以维持葡萄糖稳态的概念。哺乳动物的PDC活性会被丙酮酸脱氢酶激酶（PDKs）磷酸化而失活。丙酮酸对PDK的抑制作用促进了PDC的激活，有利于葡萄糖氧化和丙二酰辅酶A的形成：后者会抑制长链脂肪酸（LCFA）的氧化。反映LCFA高氧化速率的高线粒体乙酰辅酶A/辅酶A和NADH/NAD⁺浓度比会激活PDK，导致葡萄糖氧化受阻。在健康状态下补充葡萄糖稳态，燃料稳态，即维持稳态的适应性，是胰岛素抵抗中对血糖和血脂慢性变化反应的重要组成部分。我们提出PDKs作为组织稳态调节因子的概念，并认为长期调节单个PDKs，特别是PDK4的表达，是维持稳态的适应性的重要组成部分。我们还描述了控制各种PDK同工型表达的细胞内信号，包括过氧化物酶体增殖物激活受体和脂质的作用，它们是适应性环境中的效应器。
