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

酒精代谢对肝脏和心脏能量状态和功能的影响

• 批准号: 10679083
• 负责人: Justin Fletcher
• 金额: $ 14.09万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679083
• 关键词: ATP phosphohydrolase; Ablation; Acetaldehyde; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acute; Affect; Agreement; Alcohol abuse; Alcohol consumption; Alcohol dehydrogenase; Alcoholic Cardiomyopathy; Alcoholic Fatty Liver; Alcohols; Biochemical Reaction; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiac health; Cardiovascular Diseases; Chronic; Circulation; Cirrhosis; Citric Acid Cycle; Consumption; Cytosol; Data; Development; Diet; Doctor of Medicine; Doctor of Philosophy; Dose; Drug usage; EFRAC; Echocardiography; Educational process of instructing; Enzymes; Ethanol; Ethanol Metabolism; Functional disorder; Future; Heart; Heart Diseases; Heart failure; Hepatic; Human; Hyperlipidemia; Hypertension; Impairment; In Vitro; Infusion procedures; Knock-out; Knockout Mice; Learning; Lipids; Liquid substance; Liver; Liver Cirrhosis; Malonyl Coenzyme A; Mediating; Metabolic; Metabolism; Mitochondria; Mus; Myocardial dysfunction; NADH; Nonesterified Fatty Acids; Organ; Oxidation-Reduction; Perfusion; Peripheral; Predisposition; Process; Production; Protein Isoforms; Protocols documentation; Rodent; Role; Techniques; Tissues; Tracer; Training; Triglycerides; United States; Wild Type Mouse; alcohol effect; alcohol response; aldehyde dehydrogenases; chronic alcohol ingestion; dietary control; experimental study; fatty acid oxidation; fatty liver disease; heart function; heart metabolism; in vivo; insight; lipid biosynthesis; metabolic abnormality assessment; metabolomics; novel; oxidation; response; skills

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.

项目总结/摘要 酒精是美国最常用的药物，其使用量正在上升。酗酒会 导致酒精性脂肪肝，甚至肝硬化，因为大部分酒精是由肝脏代谢的。 在首过代谢过程中。酒精主要通过两种酶反应在肝脏中代谢 （醇脱氢酶和醛脱氢酶2），其各自将NAD+还原为NADH，从而有助于还原NAD+。 还原氧化还原态酒精消耗降低了氧化还原状态（更大的NADH/ NAD+比率）， 损害β-氧化和TCA循环。这些因素可能导致脂肪酸氧化的减少， 脂质的积累。肝脏中的代谢机制也可能使用乙酸盐作为底物来促进去乙酰化。 新生脂肪生成，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酒精会从肝脏中排出，并可被外周组织或器官利用， 就像心脏一样。心脏也受到酒精滥用的严重影响，这可能导致心脏功能障碍， 各种心血管疾病的发展，如酒精性心肌病。在心脏，醋酸 干扰脂肪酸氧化，导致ATP浓度降低，以及 甘油三酯乙酸盐可能会损害作为燃料的游离脂肪酸（FFA）的氧化，而不是通过抑制 CPT通过丙二酰辅酶A产生，但通过代谢机制胜过CPT获得游离辅酶A 导致限制FFA进入线粒体进行氧化。醋酸盐体外给药 （心脏灌注）和体内输注实验通过一种机制导致能量不足， 尚未阐明。心脏中的这种能量不足和脂质积累可能有助于 心功能不全这项建议的目的是研究这些特殊的代谢机制， 确定它们是否是酒精引起的心脏能量不足的原因。这项建议会 还确定这些机制是否负责介导酒精诱导的心功能障碍。 第二个目的是通过使用示踪剂来确定慢性酒精消费是如何变化的 以及肝脏和心脏如何代谢和使用酒精代谢物。