最新研究证明神经酰胺与非酒精性脂肪性肝病（NAFLD）的关键阶段——非酒精性脂肪性肝炎（NASH）存在相关性，神经酰胺对NASH的调控作用跃然成为精准医学的研究焦点。碱性神经酰胺酶3（ACER3）高表达于NASH患者肝组织，运用体内、体外NAFLD模型，我们发现小鼠Acer3的基因敲除或人ACER3的表达干扰可能通过上调其特异性底物18:1碳-神经酰胺（C18:1-CER），抑制肝细胞氧化应激，从而改善NASH的病理表现，包括肝组织炎症、肝纤维化、肝细胞凋亡。已知线粒体功能障碍是NAFLD肝细胞氧化应激的关键因素，本课题将深入探索ACER3/C18:1-CER对肝细胞线粒体的呼吸链复合体活性、跨膜电位、外膜通透性的影响，验证C18:1-CER对NAFLD肝细胞线粒体功能的保护作用，阐明ACER3作用于C18:1-CER调节肝细胞氧化应激影响NASH的机制，为NASH的精准防治提供新的启发。

Recent studies have demonstrated a correlation between ceramide dysregulation and non-alcoholic steatohepatitis (NASH), which is the most critical stage of non-alcoholic fatty liver disease (NAFLD), leading ceramides becoming a novel focus of Precision Medicine for NASH. Alkaline ceramidase 3 (ACER3) is upregulated in liver tissue of NASH, by establishing in vivo and in vitro model, we found that Acer3 knockout and ACER3 knockdown attenuated hepatic inflammation, hepatocyte apoptosis, and liver fibrosis during NASH by inhibiting oxidative stress in hepatocytes likely via upregulating its substrate C18:1-ceramide (C18:1-CER). Mitochondrial dysfunction is crucially important in hepatocellular oxidative stress during NAFLD, in this project, we propose to define the role of ACER3/C18:1-CER in regulating mitochondrial respiratory complex activity, membrane potential, and outer membrane permeability during NAFLD, verify the protective effects of C18:1-CER on mitochondrial dysfunction in hepatocytes, therefore elucidate the mechanism by which ACER3 and C18:1-CER regulate oxidative stress in hepatocytes and affect NASH. The project will facilitate us to understand the role of ACER3/C18:1-CER in NASH, and provide a novel approach for precision therapy of NASH.