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（申请人提供）：肝脏是酒精代谢的主要场所，也是酒精损伤的主要器官。尽管人们早已清楚乙醇在肝细胞中代谢为乙酸盐，但众所周知，乙酸盐不会在肝脏中作为燃料燃烧或直接在肝脏中转化为脂肪。乙醇产生的热量在肌肉中燃烧的知识可能会阻止人们考虑肝脏中是否发生乙酸盐的进一步代谢以及这是否可能与酒精肝病理学有关。最近，肝脏线粒体蛋白乙酰化被描述为对酒精摄入的反应。这意味着肝脏线粒体蛋白标记的分子与我们饮酒时肝脏产生的分子完全相同。我们还从遗传学中得知，许多带有乙酰化标签的线粒体蛋白都会受到这种加合物的抑制，并且具有这种修饰的小鼠在线粒体蛋白中积累会患上脂肪肝。在该提案中，提出了一种从乙醇到乙酰化肝线粒体蛋白的直接机制，并将进行测试。此外，烟酰胺核苷（一种具有增加线粒体中 NAD+ 的特性的维生素）被提议作为预防酒精源性线粒体蛋白过度乙酰化和酒精性脂肪肝发展的药物。