Neutrophil elastase in obesity-related fatty liver diseases

总结 肥胖是导致非酒精性脂肪性疾病发生的主要因素。 肝脏疾病（NAFLD），包括脂肪变性和非酒精性脂肪性肝炎（NASH）， 和肝纤维化然而，启动和破坏细胞的分子和细胞事件， 传播肥胖相关的脂肪变性，炎症损伤，和纤维化重塑， 肝脏仍然不清楚。我们观察到富含脂肪和果糖的饮食会增加 炎性中性粒细胞生成先于白细胞浸润、脂质沉积和 肝脏的炎症损伤然而，中性粒细胞弹性蛋白酶（NE）敲除（KO） 小鼠或用NE抑制剂处理的小鼠对致肥胖饮食诱导的 炎症、脂质沉积和肝纤维化。根据初步数据，我们 假设NE抑制防止肥胖诱导的促炎性中性粒细胞 通过改变NAD依赖性去乙酰化酶Sirtuin 1（Sirt 1）信号通路产生 中性粒细胞NE的缺失也激活AMP-激酶（AMPK），增加了细胞内的 过氧化物酶体增殖物激活受体α（PPARα）的表达，并增强 线粒体基因表达和脂肪酸氧化，减轻肥胖饮食- 导致肝脏脂肪变性。此外，NE的抑制或缺失减轻了 致肥胖饮食诱导的炎性巨噬细胞和辅助性T细胞17的积累 细胞、炎症损伤和肝脏中的胶原蛋白沉积。在本提案中，我们将 评估中性粒细胞中的Sirt 1，以及肝脏中的PPARα和AMPKα是否是 NE抑制对饮食诱导的NASH的有益作用。为了了解NE如何 抑制调节饮食诱导的肝纤维化重塑，我们还将探讨 中性粒细胞与其他免疫和非免疫细胞相互作用的分子基础 在肝脏中。该项目的成功完成将为分子和生物学领域提供新的视角。 抑制NE作为一种潜在的治疗方法的细胞机制 肥胖相关的脂肪肝

Summary Obesity is the primary factor that contributes to the development of nonalcoholic fatty liver diseases (NAFLD), including steatosis and nonalcoholic steatohepatitis (NASH), and fibrosis in the liver. However, the molecular and cellular events that initiate and propagate obesity-related steatosis, inflammatory damage, and fibrotic remodeling in the liver remain unclear. We observed that a fat- and fructose-enriched diet increases pro- inflammatory neutrophil production preceding leukocyte infiltration, lipid deposition, and inflammatory damage in the liver. However, neutrophil elastase (NE) knockout (KO) mice or mice treated with an NE inhibitor are resistant to obesogenic diet-induced inflammation, lipid deposition, and fibrosis in the liver. Based on our preliminary data, we hypothesize that inhibition of NE prevents obesity-induced proinflammatory neutrophil production via altering NAD-dependent deacetylase Sirtuin 1 (Sirt1) signaling pathway in neutrophils. Deletion of NE also activates AMP-kinase (AMPK), increases the expression of peroxisome proliferator-activated receptor alpha (PPARα), and enhances mitochondrial gene expression and fatty acid oxidation, attenuating obesogenic diet- induced steatosis in the liver. Furthermore, inhibition or deletion of NE mitigates obesogenic diet-induced accumulation of inflammatory macrophages and T-helper 17 cells, inflammatory damage, and collagen deposition in the liver. In this proposal, we will evaluate if Sirt1 in neutrophils, and if PPARα and AMPKα in the liver are required for the beneficial effects of NE inhibition on diet-induced NASH. To understand how NE inhibition regulates diet-induced liver fibrotic remodeling, we will also explore the molecular basis by which neutrophils interact with other immune and non-immune cells in the liver. Successful completion of this project will shed new light on molecular and cellular mechanisms by which inhibition of NE as a potential therapeutic approach for obesity-related fatty liver diseases.