Alcohol as a modulator of prefibrotic liver injury

超过50%的肝硬变死亡与酒精有关，这是一个日益严重的国家健康问题。人们普遍认为，乙醇诱导的氧化损伤可导致炎症、脂肪性肝炎、肝细胞癌和纤维化。然而，尚不清楚为什么只有一小部分酒精性肝病患者出现终末期肝硬变。同样，人们对与肥胖相关的乙醇有害影响易感性增加的因素也知之甚少。NIAAA R03的主要重点是实现对酒精性肝病严重程度的差异是否可以部分解释为酒精诱导的先前存在的肝损伤加速的基本理解。这一建议建立在我们最近的观察基础上，即饮食中维持的过表达载脂蛋白C-I的高脂血症小鼠会发生肝纤维化前损伤。将被检验的假设是，酒精可能会加剧由慢性高脂血症引发的先前存在的肝脏损伤。在这项研究中，喂饲酒精或对照饮食的正常血脂和高脂血症小鼠将被评估血浆脂类和脂蛋白的变化。活体显微镜将用于监测肝脏微循环、组织损伤和胶原沉积。组织评估将指示代谢健康和肝脏损伤的程度。这项研究具有立竿见影的意义，因为尽管高脂血症在美国很流行，但关于慢性高脂血症会导致肝脏损伤的观察结果此前并未得到重视。随着我们最近观察到慢性高脂血症会导致肝脏损伤，我们将在自发性肝损伤模型中确定酒精是否可以加速肝脏疾病的发展，在自发性肝损伤模型中，损害是由先前存在的高脂血症引发的。

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.