Alcohol as a modulator of prefibrotic liver injury

酒精被认为是超过50%的肝硬化死亡的病原体，这是一个日益增长的国家健康问题。乙醇诱导的氧化损伤可导致炎症、脂肪性肝炎、肝细胞癌和肝纤维化。然而，目前尚不清楚为什么只有酒精性肝病患者的亚群出现终末期肝硬化。同样，导致肥胖相关易感性增加的因素对乙醇的有害影响知之甚少。NIAAA R 03的主要重点是基本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诱导的预先存在的肝损伤加速。这一建议建立在我们最近的观察基础上，即高脂血症小鼠过度表达载脂蛋白C-I，维持普通饮食，发生纤维化前肝损伤。将要检验的假设是酒精可以加重由慢性高脂血症引起的既存肝损伤。在本研究中，将评价饲喂酒精或对照饮食的血脂正常和高血脂小鼠的血脂和脂蛋白变化。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损伤的程度。这项研究是立即感兴趣的，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未被认识到。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能加速自发性肝损伤模型中肝脏疾病的发展，其中损伤是由预先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.