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

• 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
• 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

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）， 和肝脏纤维化。然而，引发和发生的分子和细胞事件 传播与肥胖相关的脂肪变性、炎症损伤和纤维化重塑 肝脏尚不清楚。我们观察到，富含脂肪和果糖的饮食会增加促 炎症性中性粒细胞的产生先于白细胞浸润、脂质沉积和 肝脏炎症损伤。然而，中性粒细胞弹性蛋白酶 (NE) 敲除 (KO) 小鼠或用 NE 抑制剂治疗的小鼠对饮食诱导的肥胖具有抵抗力 肝脏炎症、脂质沉积和纤维化。根据我们的初步数据，我们 假设抑制 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。 NE 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- 诱发肝脏脂肪变性。此外，抑制或删除 NE 可以减轻 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。在本提案中，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 NE 抑制对饮食诱发的 NASH 具有有益作用。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 在肝脏中。该项目的成功完成将为分子和 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。

项目成果

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.