Mechanisms of Liver Injury in Nonalcoholic Fatty Liver Disease

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是美国最常见的肝病，目前尚无有效的治疗方法。对于这种疾病的有效治疗的发展至关重要的是了解良性脂肪肝如何进展为肝细胞损伤和炎症或脂肪性肝炎，从而导致慢性脂肪肝。 肝脏疾病该提案的目的是描述自噬的溶酶体降解途径在预防脂肪性肝炎发展中发挥核心作用的机制。我们以前的研究发现了自噬在调节细胞脂质代谢和脂肪变性中的新功能。自噬介导储存的脂质分解为游离脂肪酸（FFA），并维持线粒体？氧化，这表明自噬在脂质代谢调节的细胞途径中的核心作用。初步研究结果表明，自噬介导肝细胞对饱和FFA毒性的抵抗。此外，我们已经确定了自噬在下调炎症介质（包括FFA）对巨噬细胞的促炎激活和极化中的功能。这些发现表明，自噬功能调节细胞死亡途径和先天免疫，以响应升高的FFA，这是NAFLD发病机制的核心。基于这些和其他初步研究，我们的中心假设是自噬对肝细胞和巨噬细胞脂质代谢的影响对于防止肝脂肪变性中肝损伤和炎症的发展至关重要。我们将通过描述自噬介导的对脂质分解的影响调节肝细胞损伤和死亡以及巨噬细胞活化的机制来验证这一假设，这些研究包含在三个特定目标中。首先，我们将检验自噬通过促进饱和FFA的代谢来防止肝细胞器损伤和细胞死亡的假设。第二，我们将检验自噬通过影响脂质代谢阻断促炎巨噬细胞活化和极化来下调先天免疫反应的假设。第三，我们将检验以下假设：在肝脂肪变性的情况下，体内肝细胞和巨噬细胞中自噬的减少促进了肝损伤和炎症的发展。这些研究的目的是描绘新的范例，通过这些范例，自噬对脂质代谢功能的影响可以阻断肝细胞死亡和促炎状态的发展。研究结果将表明，肥胖和衰老引起的自噬缺陷可能有助于脂肪性肝炎的发展。这些研究的最终目标是更好地了解脂肪性肝炎发展的基本细胞机制，以设计预防和治疗人类NAFLD的新策略。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and has no proven therapy. Critical to the development of an effective treatment for this disease is an understanding of how a benign fatty liver progresses to hepatocellular injury and inflammation or steatohepatitis that leads to chronic liver disease. The objective of this proposal is to delineate mechanisms by which the lysosomal degradative pathway of autophagy plays a central role in preventing the development of steatohepatitis. Our previous investigations identified a novel function for autophagy in the regulation of cellular lipid metabolism and steatosis. Autophagy mediates the lipolytic breakdown of stored lipids into free fatty acids (FFAs) and maintains levels of mitochondrial ?-oxidation, suggesting a central role for autophagy in cellular pathways regulated by lipid metabolism. Preliminary findings demonstrate that autophagy mediates hepatocyte resistance to toxicity from saturated FFAs. In addition we have identified a function for autophagy in down regulating the proinflammatory activation and polarization of macrophages by inflammatory mediators including FFAs. These findings indicate that autophagy functions to regulate both cellular death pathways and innate immunity in response to elevated FFAs which are central to the pathogenesis of NAFLD. Based on these and other preliminary studies, our central hypothesis is that the effects of autophagy on hepatocyte and macrophage lipid metabolism are critical to prevent the development of liver injury and inflammation in hepatic steatosis. We will test this hypothesis by delineating the mechanisms by which autophagy-mediated effects on lipid breakdown regulate hepatocyte injury and death and macrophage activation in studies contained in three Specific Aims. First, we will test the hypothesis that autophagy prevents hepatocyte organelle damage and cell death by promoting the metabolism of saturated FFAs. Second, we will test the hypothesis that autophagy down regulates the innate immune response through effects on lipid metabolism that block proinflammatory macrophage activation and polarization. Third, we will test the hypothesis that decreased autophagy in hepatocytes and macrophages in vivo promotes the development of liver injury and inflammation in the setting of hepatic steatosis. The objective of these studies is to delineate novel paradigms by which the effects of autophagy on lipid metabolism function to block hepatocyte death and development of a proinflammatory state. The findings will indicate that defects in autophagy that occur with obesity and aging may contribute to the development of steatohepatitis. The ultimate goal of these investigations is to better understand the basic cellular mechanisms underlying the development of steatohepatitis in order to design new strategies to prevent and treat human NAFLD.