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.

项目摘要/摘要 酒精是美国最常用的药物，其用途正在上升。酗酒可以 导致酒精性脂肪肝病，甚至导致肝硬化，因为大多数酒精被肝脏代谢 在第一次过去的代谢中。酒精主要通过两种酶促反应在肝脏中代谢 （酒精脱氢酶和醛脱氢酶2）每种脱氢酶2）将NAD+降低到NADH，有助于A 氧化还原状态减少。饮酒可降低氧化还原状态（大NADH/ NAD+比率） 损害β氧化和TCA周期。这些因素可能导致脂肪酸氧化和 脂质的积累。肝脏中的代谢机制也可以使用乙酸盐作为底物来有助于DE Novo脂肪形成，进一步导致酒精脂肪肝病。但是，多达80％的醋酸盐 酒精代谢期间产生的肝脏逃脱，外围组织或器官可以使用此类肝脏 作为心脏。心脏也受到酗酒的严重影响，这可能导致心脏功能障碍和 各种心血管疾病的发展，例如酒精性心肌病。在心脏中，醋酸盐 干扰脂肪酸氧化，导致ATP浓度较低，以及 甘油三酸酯。醋酸盐可能会损害游离脂肪酸（FFA）的氧化物，而不是通过抑制 CPT通过Malonyl-COA生产，但通过代谢机制胜过自由COA的CPT 导致FFA进入线粒体进行氧化的限制。在体外给药 （心脏灌注）和体内输注实验通过具有的机制导致能量不足 这种能量防御和脂质积累可能有助于 心脏功能障碍。该提议的目的是检查这些特定的代谢机制，并 确定它们是否负责酒精诱发的心脏防御能源防御。该提议将 还要确定这些机制是否负责介导酒精诱导的心脏功能障碍。 第二个目的是通过使用示踪剂来确定长期饮酒的变化 加班以及肝脏和心脏如何代谢和使用酒精代谢物。