The effects of alcohol metabolism on hepatic and cardiac energy state and function

项目摘要/摘要 酒精是美国最常用的毒品，其使用量正在上升。酗酒可能会 导致酒精性脂肪肝，甚至是肝硬变，因为大部分酒精是由肝脏代谢的 在第一次新陈代谢期间。酒精在肝脏中主要通过两种酶反应进行代谢。 (酒精脱氢酶和乙醛脱氢酶2)，它们各自将NAD+还原为NADH，有助于 氧化还原状态降低。饮酒降低氧化还原状态(更大的NADH/NAD+比率)，这可能 破坏β氧化和三氯乙酸循环。这些因素可能会导致脂肪酸氧化的减少和 脂质的堆积。肝脏中的代谢机制也可能使用醋酸盐作为底物来促进 新的脂肪生成，进一步导致酒精性脂肪肝。然而，多达80%的醋酸盐 在酒精代谢过程中产生的物质逃出肝脏，并可被周围组织或器官使用，如 就像心脏一样。滥用酒精也会严重影响心脏，这会导致心脏功能不全和 各种心血管疾病的发展，如酒精性心肌病。在心脏，醋酸盐 干扰脂肪酸氧化，从而导致较低的ATP浓度，以及积累 甘油三酯。醋酸盐可能会损害作为燃料的游离脂肪酸(FFAs)的氧化，而不是通过抑制 CPT通过丙二酰辅酶A的产生，但通过代谢机制超过CPT对游离COA的竞争 从而限制了游离脂肪酸进入线粒体进行氧化。醋酸酯的体外给药 (心脏灌流)和体内输液实验通过一种机制导致能量短缺 目前尚不清楚。心脏中的这种能量不足和脂质积累可能是导致 心脏功能不全。这项建议的目的是研究这些特殊的代谢机制和 确定它们是否对酒精引起的心脏能量不足负责。这项提议将 还要确定这些机制是否对酒精引起的心功能障碍起到调节作用。 第二个目标是通过使用示踪剂来确定长期饮酒是如何变化的 加班以及肝脏和心脏如何代谢和使用酒精代谢物。

Project Summary/Abstract Alcohol is the most commonly used drug in the United States and its use is on the rise. Alcohol abuse can result in alcoholic fatty liver disease, and even cirrhosis, as the majority of alcohol is metabolized by the liver during first pass metabolism. Alcohol is primarily metabolized in the liver through two enzymatic reactions (alcohol dehydrogenase and aldehyde dehydrogenase 2) that each reduce an NAD+ to NADH, contributing to a reduced redox state. Alcohol consumption reduces the redox state (greater NADH/ NAD+ ratio) which may impair β-oxidation and the TCA cycle. These factors may result in a reduction in fatty acid oxidation and the accumulation of lipids. Metabolic mechanisms in the liver may also use acetate as substrate to contribute to de novo lipogenesis, further contributing to alcoholic fatty liver disease. However, as much as 80% of the acetate produced during alcohol metabolism escapes the liver and can be used by peripheral tissues or organs such as the heart. The heart is also severely affected by alcohol abuse, which can lead to cardiac dysfunction and the development of various cardiovascular diseases, such as alcoholic cardiomyopathy. In the heart, acetate interferes with fatty acid oxidation, which results in lower ATP concentrations, as well as the accumulation of triglycerides. Acetate may impair the oxidation of free fatty acids (FFAs) as fuel, not through the inhibition of CPT via malonyl-CoA production, but by metabolic mechanisms outcompeting CPT for free CoAs therefore resulting in the limitation of FFAs entry into the mitochondria for oxidation. Administering acetate in in vitro (heart perfusions) and in vivo infusion experiments results in an energy deficit through a mechanism that has yet to be elucidated. It is possible that this energy deficit, and lipid accumulation, in the heart are contributing to cardiac dysfunction. The aim of this proposal is to examine these particular metabolic mechanisms and determine whether they are responsible for the alcohol induced energy deficit in the heart. This proposal will also determine whether these mechanisms are responsible for mediating alcohol induced cardiac dysfunction. A secondary aim is to determine, through the use of tracers, how chronic alcohol consumption changes overtime and how the liver and heart metabolize and use alcohol metabolites.