Neutrophil elastase in obesity-related fatty liver diseases

中性粒细胞弹性蛋白酶在肥胖相关脂肪肝疾病中的作用

基本信息

批准号：
10017709
负责人：
Zhen Yue Jiang
金额：
$ 35.06万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017709
关键词：
Acetylation Adipose tissue Affect Attenuated Blood Blood Circulation Blood Vessels Bone Marrow Cardiovascular Diseases Cell Adhesion Molecules Cleaved cell Collagen Data Deacetylase Deposition Development Diet Disease Disease Resistance Enzymes Event Extravasation Fatty Liver Fatty acid glycerol esters Goals Hepatic Stellate Cell High Fat Diet Infiltration Inflammation Inflammatory Injury Insulin Resistance Knock-out Knockout Mice Leukocyte Elastase Leukocytes Light Lipids Liver Liver Fibrosis Liver diseases Longevity Mediating Metabolic Metabolic stress Molecular Molecular Weight Mus Neutrophil Infiltration Nuclear Obese Mice Obesity Oxidants Pathologic Pathway interactions Peptide Hydrolases Phenotype Phosphorylation Play Production Proteins Reporting Resistance Role SIRT1 gene Signal Pathway Signal Transduction Testing Tissues Toxic Neutrophil Wild Type Mouse adenylate kinase adiponectin base cell injury chemokine receptor cytokine design fatty acid oxidation feeding liver inflammation liver injury migration neutrophil neutrophil elastase inhibitor non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel therapeutics obesity development prevent therapeutic target

项目摘要

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.

肝感染和脂肪变性是基本的病理变化，有助于肥胖症中系统性胰岛素抵抗的发展。但是，分子和引发和传播与肥胖相关的非酒精性脂肪肝病的细胞事件（NAFLD）尚不清楚。我们报道中性粒细胞弹性酶（NE）敲除（KO）小鼠对高脂饮食（HFD）诱导的全身注射，脂肪肝和胰岛素抵抗。 WT小鼠的HFD喂养仅几天增加了促炎性嗜中性粒细胞在血管泄漏之前，白细胞浸润和肝脏中的脂肪变性。根据我们的初步数据，我们假设抑制NE 通过改变NAD依赖性，防止HFD诱导的促炎性中性粒细胞产生中性粒细胞中的脱乙酰基酶Sirtuin 1（SIRT1）信号通路。抑制NE 还增加了激活AMP-激酶的高分子重量脂联素的水平（AMPK）和脂肪酸氧化，从而减弱了HFD诱导的脂肪变性肝。此外，抑制NE还可以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）和胶原蛋白沉积肝。在此提案中，我们将评估中性粒细胞中的SIRT1和脂联素 - AMPK NE抑制对饮食诱导的有益影响需要肝脏中的途径中性粒细胞表型变化，炎症性肝损伤和脂肪变性。成功的该项目的完成将为分子和细胞机制提供新的启示抑制NE可以预防与肥胖相关的NAFLD和胰岛素抵抗。