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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

基本信息

批准号：
10506788
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
项目类别：
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/10506788
关键词：
ATP phosphohydrolase Acetaldehyde Acetate-CoA Ligase Acetates Acetyl Coenzyme A Acute Affect Alcohol abuse Alcohol consumption Alcohol dehydrogenase Alcoholic Cardiomyopathy Alcoholic Fatty Liver Alcohols Biochemical Reaction Blood Circulation Blood Pressure Cardiac Cardiac Myocytes Cardiac health Cardiovascular Diseases Chronic Cirrhosis Citric Acid Cycle Coenzyme A Consumption Cytosol Data Development Diet Doctor of Medicine Doctor of Philosophy Dose Drug usage EFRAC Echocardiography 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 Lead Learning Lipids Liquid substance Liver Liver Cirrhosis Malonyl Coenzyme A Mediating Metabolic Metabolism Mitochondria Mus Myocardial dysfunction NADH Nonesterified Fatty Acids Organ Oxidation-Reduction Oxides 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

项目摘要

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/文摘