Neutrophil elastase in obesity-related fatty liver diseases

摘要 肥胖是导致非酒精性脂肪的主要因素。 肝脏疾病(NAFLD)，包括脂肪变性和非酒精性脂肪性肝炎(NASH)， 以及肝脏纤维化。然而，分子和细胞事件启动和 在肥胖相关的脂肪变性、炎性损伤和纤维化重塑中传播 肝脏仍不清楚。我们观察到，富含脂肪和果糖的饮食增加了 炎性中性粒细胞的产生先于白细胞渗透、脂肪沉积和 肝脏的炎性损伤。然而，中性粒细胞弹性蛋白酶(NE)基因敲除(KO) 用去甲肾上腺素抑制剂治疗的小鼠对肥胖饮食诱导的小鼠具有抵抗力 肝脏的炎症、脂肪沉积和纤维化。根据我们的初步数据，我们 假设抑制去甲肾上腺素可阻止肥胖诱导的促炎性中性粒细胞 通过改变NAD依赖的脱乙酰酶Sirt1(Sirt1)信号通路在 中性粒细胞。NE的缺失还激活AMP-激酶(AMPK)，增加 过氧化物酶体增殖物激活受体α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，抑制或删除去甲肾上腺素可减轻 肥胖饮食诱导的炎性巨噬细胞和T辅助细胞17的聚集 肝脏中的细胞、炎症损伤和胶原沉积。在这项提案中，我们将 评估中性粒细胞中是否存在sirt1，以及肝脏中是否需要PPARα和AMPKα 去甲肾上腺素抑制对饮食诱导NASH的有利作用。要了解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 在肝脏里。该项目的成功完成将为分子和生物研究带来新的曙光 抑制去甲肾上腺素作为一种潜在的治疗方法的细胞机制 肥胖相关的脂肪肝疾病。

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.