Alcohol as a modulator of prefibrotic liver injury

酒精被认为是50%以上肝硬化死亡的病因，肝硬化是一个日益严重的国家健康问题。乙醇诱导的氧化损伤可引起炎症、脂肪性肝炎、肝细胞癌和纤维化，已被广泛接受。然而，目前尚不清楚为什么只有酒精性肝病患者亚群出现终末期肝硬化。同样，导致肥胖对乙醇有害影响的易感性增加的因素也知之甚少。本NIAAA R03的主要目的是了解酒精性肝病严重程度的差异是否可以部分解释为酒精引起的先前存在的肝损伤加速。这一建议建立在我们最近的观察基础上，即在食物中过度表达载脂蛋白C-I的合并高脂血症小鼠会发生纤维化前肝损伤。即将被验证的假设是酒精会加重由慢性高脂血症引起的原有肝损伤。在这项研究中，正常血脂和高脂血症小鼠喂食酒精或对照饮食，将评估血浆脂质和脂蛋白的变化。活体显微镜将用于监测肝脏微循环、组织损伤和胶原沉积。组织评估将显示代谢健康状况和肝损伤程度。这项研究具有直接意义，因为虽然高脂血症在美国是流行病，但慢性高脂血症可导致肝损伤的观察结果以前没有得到重视。根据我们最近的观察，慢性高脂血症可导致肝损伤，我们将确定酒精是否会在自发性肝损伤模型中加速肝脏疾病的发展，其中损伤是由先前存在的高脂血症引起的。

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.