Ragavan Mukundan, McLeod Marc A, Rushin Anna, Merritt Matthew E
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, United States.
Front Physiol. 2022 Feb 7;13:832403. doi: 10.3389/fphys.2022.832403. eCollection 2022.
The role of ketones in metabolic health has progressed over the past two decades, moving from what was perceived as a simple byproduct of fatty acid oxidation to a central player in a multiplicity of disease states. Previous work with hyperpolarized (HP) C has shown that ketone production can be detected when using precursors that labeled acetyl-CoA at the C1 position, often in tissues that are not normally recognized as ketogenic. Here, we assay metabolism of HP [2-C]pyruvate in the perfused mouse liver, a classic metabolic testbed where nutritional conditions can be precisely controlled. Livers perfused with long-chain fatty acids or the medium-chain fatty acid octanoate showed no evidence of ketogenesis in the C spectrum. In contrast, addition of dichloroacetate, a potent inhibitor of pyruvate dehydrogenase kinase, resulted in significant production of both acetoacetate and 3-hydroxybutyrate from the pyruvate precursor. This result indicates that ketones are readily produced from carbohydrates, but only in the case where pyruvate dehydrogenase activity is upregulated.
在过去二十年中，酮类在代谢健康中的作用不断发展，从被认为是脂肪酸氧化的简单副产物转变为多种疾病状态中的核心参与者。先前使用超极化（HP）碳的研究表明，当使用在C1位置标记乙酰辅酶A的前体时，可以检测到酮的产生，这通常发生在通常不被认为是生酮的组织中。在这里，我们在灌注的小鼠肝脏中检测HP [2-C]丙酮酸的代谢，这是一个经典的代谢试验平台，营养条件可以精确控制。用长链脂肪酸或中链脂肪酸辛酸灌注的肝脏在C谱中没有生酮的迹象。相反，添加丙酮酸脱氢酶激酶的有效抑制剂二氯乙酸会导致丙酮酸前体大量产生乙酰乙酸和3-羟基丁酸。这一结果表明，酮类很容易由碳水化合物产生，但仅在丙酮酸脱氢酶活性上调的情况下。
