Mechanisms of Liver Injury in Nonalcoholic Fatty Liver Disease

非酒精性脂肪肝的肝损伤机制

• 批准号: 8697041
• 负责人: Mark J Czaja
• 金额: $ 36.32万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697041
• 关键词: Adipose tissue; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Autophagocytosis; Benign; Cell Death; Cell Line; Cessation of life; Defect; Degradation Pathway; Dependovirus; Development; Disease; Fatty Liver; Functional disorder; Funding; Genes; Genetic; Goals; Hepatic; Hepatocyte; Human; Immune response; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Knock-out; Lipids; Lipopolysaccharides; Liver; Liver Failure; Liver diseases; Macrophage Activation; Mediating; Metabolism; Mitochondria; Molecular; Mus; Natural Immunity; Nonesterified Fatty Acids; Obesity; Organelles; Pathogenesis; Pathway interactions; Phenotype; Play; Prevention; Resistance; Role; Steatohepatitis; Stress; Testing; Toxic effect; Triglycerides; United States; base; cell growth regulation; chronic liver disease; design; effective therapy; fatty acid metabolism; in vivo; in vivo Model; inhibition of autophagy; insight; lipid metabolism; liver inflammation; liver injury; loss of function; macrophage; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel strategies; outcome forecast; overexpression; oxidation; prevent; response; therapy development

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.

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是美国最常见的肝病，目前还没有得到证实的治疗方法。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，从而导致慢性脂肪性肝炎，这对开发这种疾病的有效治疗方法至关重要。 肝病。这项建议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肪代谢和脂肪变性中的一个新功能。自噬介导储存的脂类分解为游离脂肪酸(FFA)，并维持线粒体氧化水平，这表明自噬在脂代谢调节的细胞通路中发挥着核心作用。初步研究结果表明，自噬介导了肝细胞对饱和脂肪酸毒性的抵抗。此外，我们还确定了自噬在下调包括游离脂肪酸在内的炎性介质对巨噬细胞的促炎激活和极化方面的作用。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FFAs，这是NAFLD发病的核心。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代谢的影响对于防止肝脂肪变性中的肝损伤和炎症的发展至关重要。在包含三个特定目标的研究中，我们将通过描述自噬介导的脂质分解调节肝细胞损伤和死亡以及巨噬细胞激活的机制来检验这一假说。首先，我们将验证自噬通过促进饱和脂肪酸的代谢来防止肝细胞细胞器损伤和细胞死亡的假设。其次，我们将验证这样的假设：自噬通过对脂质代谢的影响来下调先天免疫反应，从而阻止促炎巨噬细胞的激活和极化。第三，我们将验证在肝脂肪变性的背景下，体内肝细胞和巨噬细胞自噬减少促进肝损伤和炎症发展的假说。这些研究的目的是描绘新的范例，通过自噬对脂代谢功能的影响来阻止肝细胞死亡和促炎状态的发展。这些发现将表明，肥胖和衰老导致的自噬缺陷可能会导致脂肪性肝炎的发生。这些研究的最终目的是为了更好地了解脂肪性肝炎发生的基本细胞机制，以便设计新的策略来预防和治疗人类非酒精性脂肪肝。