Sugden M C, Bulmer K, Holness M J
Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London E1 4NS, U.K.
Biochem Soc Trans. 2001 May;29(Pt 2):272-8. doi: 10.1042/0300-5127:0290272.
Fuel metabolism is highly regulated to ensure adequate energy for cellular function. The contribution of the major metabolic fuels--glucose, lactate and fatty acids (FAs)--often reflects their circulating levels. In addition, regulatory cross-talk and fuel-induced hormone secretion ensures appropriate and co-ordinate fuel utilization. Because its activity can either determine or reflect fuel preference (carbohydrate versus fat), the pyruvate dehydrogenase complex (PDC) occupies a pivotal position in fuel cross-talk. Active PDC permits glucose oxidation and allows the formation of mitochondrially derived intermediates (e.g. malonyl-CoA and citrate) that reflect fuel abundance. FA oxidation suppresses PDC activity. PDC inactivation by phosphorylation is catalysed by pyruvate dehydrogenase kinases (PDKs) 1-4, which are regulated differentially by metabolite effectors. Most tissues contain at least two and often three of the PDK isoforms. We develop the hypothesis that PDK4 is a "lipid status"-responsive PDK isoform facilitating FA oxidation and signalling through citrate formation. Substrate interactions at the level of gene transcription extend glucose-FA interactions to the longer term. We discuss potential targets for substrate-mediated transcriptional regulation in relation to selective PDK isoform expression and the influence of altered PDK isoform expression in fuel sensing, selection and utilization.
燃料代谢受到高度调节，以确保为细胞功能提供充足的能量。主要代谢燃料——葡萄糖、乳酸和脂肪酸（FAs）的贡献通常反映它们的循环水平。此外，调节性相互作用和燃料诱导的激素分泌确保了适当且协调的燃料利用。由于丙酮酸脱氢酶复合体（PDC）的活性既可以决定也可以反映燃料偏好（碳水化合物与脂肪），因此它在燃料相互作用中占据关键地位。活跃的PDC允许葡萄糖氧化，并允许形成反映燃料丰度的线粒体衍生中间体（如丙二酰辅酶A和柠檬酸）。脂肪酸氧化会抑制PDC活性。丙酮酸脱氢酶激酶（PDKs）1 - 4催化磷酸化导致的PDC失活，它们受到代谢物效应物的不同调节。大多数组织至少含有两种，通常是三种PDK同工型。我们提出一个假说，即PDK4是一种“脂质状态”响应性PDK同工型，通过柠檬酸形成促进脂肪酸氧化和信号传导。基因转录水平上的底物相互作用将葡萄糖 - 脂肪酸相互作用扩展到更长期。我们讨论了与选择性PDK同工型表达相关的底物介导转录调控的潜在靶点，以及改变的PDK同工型表达在燃料感知、选择和利用中的影响。
