Pathogenesis and Novel Therapeutic Targets of Fatty Liver Disease and Cancer

脂肪肝疾病和癌症的发病机制和新的治疗靶点

• 批准号: 10701535
• 负责人: bin gao
• 金额: $ 131.31万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701535
• 关键词: 5' -AMP-activated protein kinase; Aging; Alcoholic Hepatitis; Alcoholic Liver Diseases; Anti-Inflammatory Agents; Automobile Driving; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Disease Progression; Ethanol; Ethanol Metabolism; Experimental Models; Failure; Fatty Liver; Genes; Goals; Immune; Immunohistochemistry; Immunologics; Inflammatory; Injury; Laboratories; Liver; Liver diseases; Malignant neoplasm of liver; MicroRNAs; Myelogenous; Neutrophil Infiltration; Pathogenesis; Patients; Pattern; Phenotype; Production; base; fatty liver disease; feeding; intrahepatic; lipid metabolism; liver inflammation; liver injury; mouse model; neutrophil; new therapeutic target; transcriptome sequencing; translational study

Our laboratory has been actively studying the pathogenesis of alcoholic liver disease, focusing on characterization of inflammatory cells in alcoholic hepatitis. we have identified two distinct histopathological phenotypes based on liver immune phenotyping are observed in severe alcoholic hepatitis (SAH) patients. Intrahepatic neutrophil infiltration has been implicated in SAH pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neuhi), but low levels of CD8+ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neuhi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.

本实验室一直在积极研究酒精性肝病的发病机制，重点研究酒精性肝炎中炎性细胞的特征。在重型酒精性肝炎(SAH)患者中观察到了基于肝脏免疫表型的两种不同的组织病理表型。 肝内中性粒细胞浸润与SAH的发病机制有关，然而，中性粒细胞诱导SAH损伤的机制尚不清楚。这项翻译研究旨在描述肝内中性粒细胞的渗透模式及其在SAH发病机制中的作用。移植肝脏的免疫组织化学分析发现了两种SAH表型，尽管临床表现相似，一种是肝内中性粒细胞(NeuHi)高，但CD8+T细胞水平低，反之亦然。RNA-Seq分析表明，中性粒细胞胞浆因子1(NCF1)是控制中性粒细胞ROS产生的关键因子，它上调了中性粒细胞ROS的表达，并与肝脏炎症和疾病进展相关。为了具体研究AH患者NeuHi和肝脏损伤的相关机制，我们使用慢性+狂饮酒精喂养的小鼠模型，发现髓系特异性的Ncf1基因缺失可以消除乙醇诱导的肝脏炎症和脂肪变性。RNA-Seq分析和实验模型的数据显示，中性粒细胞依赖的NCF1依赖的ROS通过抑制AMP激活的蛋白激酶(脂代谢的关键调节因子)和microRNA-223(关键的抗炎和抗纤维化的microRNA)而促进酒精性肝炎(AH)。总之，在SAH患者中观察到了基于肝脏免疫表型的两种不同的组织病理表型，这表明在这些患者中导致肝损伤和/或衰竭的单独机制。