Neutrophil elastase in obesity-related fatty liver diseases

肝脏炎症和脂肪变性是导致 全身性胰岛素抵抗在肥胖中的发展。然而，分子和 启动和传播肥胖相关非酒精性脂肪性肝病的细胞事件 (NAFLD)仍不清楚。我们报道了中性粒细胞弹性蛋白酶(NE)基因敲除(KO)小鼠 对高脂饮食(HFD)引起的全身炎症、脂肪肝和 胰岛素抵抗。WT小鼠仅喂食HFD几天会增加促炎作用 中性粒细胞产生先于血管渗漏、白细胞浸润和 肝脏脂肪变性。根据我们的初步数据，我们假设NE的抑制作用 通过改变NAD依赖抑制HFD诱导的促炎性中性粒细胞产生 中性粒细胞中的Sirt1信号通路。去甲肾上腺素抑制作用 还会增加激活AMP-Kinase的高分子脂联素的水平 (AMPK)和脂肪酸氧化，从而减轻HFD诱导的大鼠脂肪变性 肝脏。此外，抑制NE还可改善高脂高碳水化合物饮食(HFHCD)。 诱发脂肪变性、非酒精性脂肪性肝炎(NASH)和胶原沉积 肝脏。在这项提案中，我们将评估中性粒细胞中的Sirt1和脂联素-AMPK 抑制去甲肾上腺素对饮食诱导的有益作用需要肝脏途径 中性粒细胞表型改变，炎症性肝损伤和脂肪变性。成功 该项目的完成将为分子和细胞机制提供新的线索 抑制去甲肾上腺素可预防肥胖相关的NAFLD和胰岛素抵抗。

Liver inflammation and steatosis are fundamental pathological changes that contribute to the development of systemic insulin resistance in obesity. However, the molecular and cellular events that initiate and propagate obesity-related non-alcoholic fatty liver disease (NAFLD) remain unclear. We reported that neutrophil elastase (NE) knockout (KO) mice are resistant to a high-fat diet (HFD)-induced systemic inflammation, fatty liver, and insulin resistance. HFD feeding of WT mice for only a few days increases proinflammatory neutrophil production preceding vascular leakage, leukocyte infiltration and steatosis in the liver. Based on our preliminary data, we hypothesize that inhibition of NE prevents HFD-induced proinflammatory neutrophil production via altering NAD-dependent deacetylase Sirtuin 1 (Sirt1) signaling pathway in neutrophils. Inhibition of NE also increases the levels of high-molecular-weight adiponectin that activates AMP-kinase (AMPK) and fatty acid oxidation, thus attenuating HFD-induced steatosis in the liver. In addition, inhibition of NE also ameliorated high-fat high-carb diet (HFHCD)- induced steatosis, nonalcoholic steatohepatitis (NASH) and collagen deposition in the liver. In this proposal, we will evaluate if Sirt1 in neutrophils and the adiponectin – AMPK pathway in the liver are required for the beneficial effects of NE inhibition on diet-induced neutrophil phenotypic changes, inflammatory liver damage and steatosis. Successful completion of this project will shed new light on molecular and cellular mechanisms by which inhibition of NE prevent obesity-related NAFLD and insulin resistance.