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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：
10477430
负责人：
Zhen Yue Jiang
金额：
$ 41.52万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477430
关键词：
Acetylation Affect Attenuated Biogenesis CXCL5 gene Catabolism Cell Adhesion Molecules Cells 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 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 fatty liver disease feeding injury and repair lipid metabolism liver development liver inflammation 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.

总结

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice.

DOI：
10.3390/cells11152288
发表时间：
2022-07-25
期刊：
CELLS
影响因子：
6
作者：
Ushakumari, Chinchu Jagadan;Zhou, Qiong L.;Wang, Yu-Hua;Na, Sijia;Rigor, Michael C.;Zhou, Cindy Y.;Kroll, Max K.;Lin, Benjamin D.;Jiang, Zhen Y.
通讯作者：
Jiang, Zhen Y.