Role of Mitochondrial Protein Acetylation in the Liver Pathology of Alcohol

简介（申请人提供）：肝脏是酒精代谢的主要部位，是酒精损伤的主要器官。虽然人们早就知道乙醇在肝细胞中代谢成醋酸盐，但众所周知，醋酸盐不会在肝脏中作为燃料燃烧，也不会直接转化为肝脏中的脂肪。乙醇的热量在肌肉中燃烧，这一知识可能抑制了人们考虑醋酸盐是否会在肝脏中进一步代谢，以及这是否与酒精肝病理有关。最近，肝脏线粒体蛋白乙酰化已被描述为对酒精摄入的反应。这意味着肝脏线粒体蛋白被标记的分子与我们喝酒时肝脏产生的分子完全相同。我们还从遗传学上知道，许多带有乙酰化标签的线粒体蛋白质受到这种加合物的抑制，线粒体蛋白质中积累了这种修饰的老鼠会患上脂肪肝。在这个提议中，提出了一个从乙醇到乙酰化肝脏线粒体蛋白的直接机制，并将进行测试。此外，烟酰胺核苷是一种维生素，具有增加线粒体中NAD+的特性，被认为是一种防止酒精来源的线粒体蛋白超乙酰化和酒精性脂肪肝发展的药物。

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.