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：
10264057
负责人：
Zhen Yue Jiang
金额：
$ 41.66万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264057
关键词：
Acetylation Affect Attenuated Biogenesis CXCL5 gene Catabolism Cell Adhesion Molecules Cells Cleaved cell Clinical Research Clinical Trials Collagen Data Deacetylase Deposition Development Diet Disease Enzymes Event Extracellular Matrix Fatty Liver Fatty acid glycerol esters Fibrosis Fructose Gene Expression Genes High Fat Diet Immune Impairment Infiltration Inflammation Inflammatory Insulin Resistance Knock-out Knockout Mice Lead Leukocyte Elastase Leukocytes Light Lipids Liver Liver Fibrosis Liver diseases Longevity Macrophage Activation Metabolic Metabolic Diseases Metabolic Pathway Metabolic stress Mitochondria Molecular Molecular Weight Mus Neutrophil Infiltration Neutrophilic Infiltrate Nuclear Obesity Oxidants PPAR alpha Pathologic Pathway interactions Peptide Hydrolases Phenotype Phosphorylation Plasma Play Process Production Proteins Resistance Role SIRT1 gene Signal Pathway Signal Transduction Testing Therapeutic Tissues Up-Regulation adenylate kinase adiponectin base chemokine chemokine receptor cytokine design diet-induced obesity fatty acid oxidation feeding injury and repair lipid metabolism liver development liver injury macrophage mouse model neutrophil neutrophil elastase inhibitor new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel therapeutic intervention obesity development obesity prevention obesogenic progenitor repaired vascular injury

项目摘要

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.

概括肥胖是导致非酒精性脂肪肝发展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），然而，引发和肝脏纤维化的分子和细胞事件。传播与肥胖相关的脂肪变性、炎症损伤和纤维化重塑我们观察到富含脂肪和果糖的饮食会增加促肝脏功能。炎症性中性粒细胞的产生先于白细胞浸润、脂质沉积和然而，中性粒细胞弹性蛋白酶（NE）敲除（KO）会导致肝脏炎症损伤。小鼠或用 NE 抑制剂治疗的小鼠对饮食诱发的肥胖具有抵抗力根据我们的初步数据，我们发现肝脏中的炎症、脂质沉积和纤维化。抑制 NE 可预防肥胖诱导的促炎性中性粒细胞通过改变 NAD 依赖性脱乙酰酶 Sirtuin 1 (Sirt1) 信号通路来产生中性粒细胞的缺失也会激活 AMP 激酶 (AMPK)，增加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- 此外，抑制或缺失 NE 可减轻肝脏脂肪变性。肥胖饮食诱导炎症巨噬细胞和 T 辅助细胞 17 的积累细胞、炎症损伤和肝脏中的胶原沉积。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 NE 抑制对饮食诱发的 NASH 的有益影响了解 NE 如何发挥作用。抑制调节饮食诱导的肝纤维化重塑，我们还将探索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该项目的成功完成将为分子和肝脏研究提供新的线索。抑制 NE 作为潜在治疗方法的细胞机制肥胖相关的脂肪肝疾病。