Effect of impaired macrophage autophagy on the development of fatty liver disease

巨噬细胞自噬受损对脂肪肝疾病发展的影响

• 批准号: 8398163
• 负责人: Kun Liu
• 金额: $ 5.67万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-11 至 2014-02-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398163
• 关键词: Address; Adipose tissue; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Autophagocytosis; Benign; Cell Line; Cells; Data; Degradation Pathway; Deposition; Development; Diet; Disease; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Goals; Hepatic; Hepatocyte; Immune response; Impairment; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Injury to Liver; Insulin Resistance; Investigation; Knock-out; Laboratories; Lead; Link; Lipids; Lipolysis; Lipopolysaccharides; Liver; Liver diseases; Macrophage Activation; Mediating; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Natural Immunity; Nonesterified Fatty Acids; Obesity; Obesity associated disease; Pathway interactions; Play; Prevention; Prevention approach; Regulation; Role; Serum; Steatohepatitis; Stimulus; Testing; Tissues; United States; base; chronic liver disease; effective therapy; feeding; in vivo; in vivo Model; inhibition of autophagy; lipid metabolism; macrophage; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel strategies; outcome forecast; oxidation; prevent; response

DESCRIPTION (provided by applicant): Macrophage-mediated inflammation underlies the development of the metabolic syndrome and its associated diseases, including nonalcoholic fatty liver disease (NAFLD). 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. Macrophages can be activated by various stimuli and undergo polarization into proinflammatory M1 or anti-inflammatory M2 macrophages. A preponderance of M1 macrophages promotes tissue inflammation and occurs in adipose tissue in obesity-related diseases. Central to NAFLD development is an increase in serum free fatty acids (FFAs) and their excessive deposition in tissues. Saturated FFAs can trigger M1 macrophage polarization, suggesting that alterations in the metabolism of these FFAs may modulate the inflammatory response in NAFLD. 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 lipid metabolism. Autophagy mediates the lipolytic breakdown of stored lipids into free fatty acids and maintains levels of mitochondrial ¿-oxidation, suggesting a critical role for autophagy in cellular pathways regulated by lipid metabolism. In addition, preliminary studies 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 innate immunity in response to elevated FFAs that occur with NAFLD. Based on these and other preliminary studies, our central hypothesis is that the effects of autophagy on 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 macrophage activation in studies contained in three Specific Aims. First, we will test the hypothesis that autophagy down regulates the innate immune response by blocking proinflammatory macrophage activation and polarization. Second, we will examine whether autophagy inhibits proinflammatory macrophage activation and polarization through effects on lipid metabolism. Third, we will test the hypothesis that decreased autophagy in 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 macrophage lipid metabolism function to block development of a proinflammatory state. The findings will suggest that the impairment in autophagy that occurs with obesity and aging leads to the development of steatohepatitis by effects on the immune response. By uncovering this new mechanism for the development of steatohepatitis, novel approaches to the prevention and treatment of NAFLD may be found. PUBLIC HEALTH RELEVANCE: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the United States and a leading cause of chronic liver disease. The pathophysiology of this disease is unclear and as a result it has no established treatment. It is the objective of this proposal to understand the mechanisms by which liver injury occurs in the setting of a fatty liver to spur new approaches for the prevention and treatment of NAFLD.

描述（由申请人提供）：巨噬细胞介导的炎症是代谢综合征及其相关疾病（包括非酒精性脂肪性肝病（NAFLD））发展的基础。NAFLD是美国最常见的肝脏疾病，目前尚无有效的治疗方法。开发有效治疗这种疾病的关键是了解良性脂肪肝如何进展为肝细胞损伤和炎症或导致慢性肝病的脂肪性肝炎。巨噬细胞可被各种刺激激活，并极化为促炎性M1或抗炎性M2巨噬细胞。M1巨噬细胞的优势促进组织炎症，并发生在肥胖相关疾病的脂肪组织中。NAFLD发展的核心是血清游离脂肪酸（FFA）的增加及其在组织中的过度沉积。饱和的游离脂肪酸可以触发M1巨噬细胞极化，这表明这些游离脂肪酸代谢的改变可以调节NAFLD中的炎症反应。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脂质代谢中的一种新功能。自噬介导储存的脂质分解为游离脂肪酸，并维持线粒体氧化水平，这表明自噬在细胞内的关键作用。 由脂质代谢调节的途径。此外，初步研究已经确定了自噬在下调巨噬细胞的促炎性激活和极化中的功能，所述促炎性激活和极化是由包括FFA的炎性介质引起的。这些发现表明，自噬功能调节先天免疫，以响应NAFLD发生的FFA升高。基于这些和其他初步研究，我们的中心假设是自噬对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的中。首先，我们将检验自噬通过阻断促炎性巨噬细胞活化和极化下调先天免疫反应的假设。其次，我们将研究自噬是否通过影响脂质代谢抑制促炎性巨噬细胞活化和极化。第三，我们将检验巨噬细胞体内自噬减少促进肝脂肪变性背景下肝损伤和炎症发展的假设。客观 这些研究的目的是描述新的范例，通过这些范例，自噬对巨噬细胞脂质代谢的作用阻断促炎状态的发展。研究结果表明，肥胖和衰老引起的自噬损伤通过影响免疫反应导致脂肪性肝炎的发展。通过揭示这种脂肪性肝炎发展的新机制，可能会发现预防和治疗NAFLD的新方法。 公共卫生相关性：非酒精性脂肪性肝病（NAFLD）是美国最常见的肝病，也是慢性肝病的主要原因。这种疾病的病理生理学尚不清楚，因此没有既定的治疗方法。本提案的目的是了解脂肪肝背景下发生肝损伤的机制，以促进预防和治疗NAFLD的新方法。