Alcohol as a modulator of prefibrotic liver injury

酒精作为纤维化前肝损伤的调节剂

• 批准号: 6532405
• 负责人: MARK G CLEMENS
• 金额: $ 6.5万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532405
• 关键词: alcoholic beverage consumption; alcoholic liver cirrhosis; alcoholism /alcohol abuse; alcohols; blood chemistry; blood lipid; blood lipoprotein; blood lipoprotein metabolism; collagen; disease /disorder etiology; fibrosis; fluorescence microscopy; gel electrophoresis; genetically modified animals; histology; hyperlipidemia; immunologic assay /test; intravital microscopy; laboratory mouse; liver; liver disorder; microcirculation; oxidative stress; oxidized lipid; pathologic process

Alcohol is implicated as the etiologic agent in greater than 50% of deaths due to liver cirrhosis, a growing national health concern. It is widely accepted that ethanol-induced oxidative injury can result in inflammation, steatohepatitis, hepatocellular carcinoma and fibrosis. However, it is unknown why only a subpopulation of alcoholic liver disease patients present with end stage liver cirrhosis. Likewise, factors contributing to increased obesity-related susceptibility to the deleterious effects of ethanol are poorly understood. This NIAAA R03 has as its primary focus to achieve a basic understanding of whether differences in the severity of alcoholic liver disease can be explained, in part, by alcoholinduced acceleration of preexisting liver injury. This proposal builds on our recent observation that combined hyperlipidemic mice that overexpress apolipoprotein C-I maintained on a chow diet develop prefibrotic liver injury. The hypothesis that will be tested is that alcohol can exacerbate preexisting liver injury initiated by chronic hyperlipidemia. In this study, normolipidemic and hyperlipidemic mice fed alcohol or a control diet will be evaluated for changes in plasma lipids and lipoproteins. Intravital microscopy will be used to monitor liver microcirculation, tissue damage and collagen deposition. Tissue evaluation will indicate the metabolic health and extent of liver injury. This study is of immediate interest because while hyperlipidemia is pandemic in the US, the observation that chronic hyperlipidemia can result in liver injury was previously unappreciated. With our recent observation that chronic hyperlipidemia can result in liver injury we will determine whether alcohol can accelerate the development of liver disease in a spontaneous liver injury model where the damage is initiated by preexisting hyperlipidemia.

酒精被认为是由于肝硬化而导致的50％以上死亡的病因学剂，这是一个日益增长的国家健康问题。人们普遍认为，乙醇诱导的氧化损伤会导致炎症，脂肪性肝炎，肝细胞癌和纤维化。但是，尚不清楚为什么只有饮酒肝病患者的亚群就有末期肝肝硬化。同样，对肥胖相关的易感性增加的因素对乙醇的有害作用的敏感性也很差。该NIAAA R03的主要重点是基本了解是否可以通过酗酒的肝损伤加速来解释酒精性肝病严重程度的差异。这项提案是基于我们最近的观察结果，即高脂小鼠过表达载脂蛋白C-I在食物饮食上保持纤维化肝损伤。将要检验的假设是，酒精会加剧慢性高脂血症引发的肝损伤。在这项研究中，将评估喂养酒精或对照饮食的正常脂肪和高脂小鼠的血浆脂质和脂蛋白的变化。插入显微镜将用于监测肝微循环，组织损伤和胶原蛋白沉积。组织评估将表明肝损伤的代谢健康和程度。这项研究引起了直接的兴趣，因为在美国高脂血症是大流行的，但以前对慢性高脂血症可能导致肝损伤的观察结果以前是未见的。通过我们最近的观察，慢性高脂血症可能导致肝损伤，我们将确定酒精是否可以加速自发性肝损伤模型中肝病的发展，在这种模型中，通过先前存在的高脂血症引发了损害。