Role of Mitochondrial Protein Acetylation in the Liver Pathology of Alcohol

线粒体蛋白乙酰化在酒精肝脏病理学中的作用

• 批准号: 8700872
• 负责人: Charles M Brenner
• 金额: $ 17.05万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700872
• 关键词: Acetaldehyde; Acetates; Acetylation; Acetyltransferase; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; American; Blood; Burn injury; Calories; Carbon; Carbon Dioxide; Communities; Cytosol; Data; Deacetylase; Development; Enzymes; Ethanol; Ethanol Metabolism; Fatty Liver; Fatty acid glycerol esters; Genetic; Health; Hepatocyte; Human; In Situ; Knowledge; Ligase; Link; Liver; Liver Mitochondria; Lysine; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modification; Mus; Muscle; Muscle Mitochondria; NADH; Organ; Pathology; Pathway interactions; Phenotype; Process; Production; Property; Protein Acetylation; Proteins; Radioactive; Research; Research Personnel; Risk; Role; Site; Testing; Vitamins; adduct; alcohol abuse therapy; alcohol research; alcohol response; design; improved; injured; lipid biosynthesis; lipid metabolism; nicotinamide-beta-riboside; prevent; problem drinker; public health relevance; research study

DESCRIPTION (provided by applicant): Liver is the primary site of alcohol metabolism and is the primary organ that is injured by alcohol. Though it has long been clear that ethanol is metabolized to acetate in hepatocytes, it is known that the acetate isn't burned as fuel in the liver or directly converted to fat in the liver. The knowledge that the calories from ethanol are burned in the muscle may have inhibited people from considering whether any further metabolism of acetate occurs in the liver and whether this could be linked to alcohol hepatopathology. Recently, liver mitochondrial protein acetylation has been described in response to alcohol ingestion. This means that liver mitochondrial proteins are tagged with the exact same molecule that liver produces when we drink alcohol. We also know from genetics that many mitochondrial proteins with the acetylation tag are inhibited by this adduct and that mice that have this modification accumulate in mitochondrial proteins get fatty liver. In this proposal, a straightforward mechanism from ethanol to acetylated liver mitochondrial proteins is proposed and will be tested. Moreover, nicotinamide riboside, a vitamin that has the property of increasing NAD+ in mitochondria, is proposed as an agent to protect against the development of alcohol-derived mitochondrial protein hyperacetylation and alcoholic fatty liver.

描述（由申请人提供）：肝脏是酒精代谢的主要部位，也是酒精损伤的主要器官。虽然乙醇在肝细胞中被代谢为乙酸盐已经很清楚，但已知乙酸盐在肝脏中不作为燃料燃烧，也不直接转化为肝脏中的脂肪。乙醇中的卡路里在肌肉中燃烧的知识可能会抑制人们考虑乙酸盐是否在肝脏中发生进一步代谢，以及这是否与酒精肝脏病理学有关。最近，肝线粒体蛋白乙酰化已被描述为响应酒精摄入。这意味着肝脏线粒体蛋白质被标记有与我们饮酒时肝脏产生的完全相同的分子。我们还从遗传学中知道，许多带有乙酰化标签的线粒体蛋白质被这种加合物抑制，并且具有这种修饰的小鼠在线粒体蛋白质中积累，从而获得脂肪肝。在这个建议中，提出了一个简单的机制，从乙醇乙酰化肝线粒体蛋白质，并将进行测试。此外，烟酰胺核苷，一种具有增加线粒体中NAD+的性质的维生素，被提出作为防止酒精衍生的线粒体蛋白质过度乙酰化和酒精性脂肪肝发展的试剂。