Pathogenesis and Novel Therapeutic Targets of Fatty Liver Disease and Cancer

本实验室一直在积极研究酒精性肝病的发病机制，重点是酒精性肝炎中炎性细胞的特征。我们已经鉴定了两种不同的基于肝脏免疫表型的组织病理学表型，在重度酒精性肝炎（SAH）患者中观察到。 肝内中性粒细胞浸润与SAH的发病机制有关，然而，嗜中性粒细胞诱导的SAH损伤的机制仍然不清楚。这项翻译研究的目的是描述肝内中性粒细胞浸润的模式及其参与SAH的发病机制。免疫组织化学分析表明，尽管有相似的临床表现，SAH的肝脏两种表型，高肝内中性粒细胞（Neuhi），但低水平的CD 8 + T细胞，反之亦然。RNA-Seq分析表明，中性粒细胞胞质因子1（NCF 1），控制嗜中性粒细胞ROS产生的关键因素，上调，并与肝脏炎症和疾病进展。为了具体研究AH患者和肝损伤中与Neuhi相关的机制，我们使用了慢性加酗酒乙醇喂养的小鼠模型，发现骨髓特异性Ncf 1基因缺失消除了乙醇诱导的肝脏炎症和脂肪变性。RNA-Seq分析和来自实验模型的数据显示，嗜中性粒细胞NCF 1依赖性ROS通过抑制AMP激活的蛋白激酶（脂质代谢的关键调节因子）和microRNA-223（一种关键的抑制剂和抗纤维化microRNA）促进酒精性肝炎（AH）。总之，在SAH患者中观察到基于肝脏免疫表型的两种不同的组织病理学表型，这表明在这些患者中驱动肝损伤和/或衰竭的单独机制。

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.