Protectin DX对非酒精性脂肪性肝病的保护作用及其机制研究

Nonalcoholic fatty liver disease (NAFLD) has been one of the most common causes of chronic liver diseases in China. However, its exact pathogenesis remains unclear and there has been no effective pharmacological therapy. Protectin DX (PDX) is produced by the sequential lipoxygenation of docosahexaenoic acid (DHA). In our previous study, we found that administration of PDX to high fat diet (HFD)-fed mice resulted in reduced hepatic triglyceride contents and increased hepatic AMPK phosphorylation which suggested the protection effect of PDX on NAFLD. Moreover, accumulating evidence shows that AMPK activation may reduce NAFLD by several mechanisms. Therefore, to confirm the effects of PDX on the progression of NAFLD, we will further focus on: 1) The role of PDX in regulating hepatic steatosis and steatohepatitis in different animal models. 2) Whether PDX regulates NAFLD by AMPK activation in in vivo and in vitro studies. 3) Whether PDX improves NAFLD by inducing autophagy through AMPK-mTOR signal pathway. This study will provide a promising approach for the treatment of NAFLD.

非酒精性脂肪性肝病（NAFLD）已成为我国最为常见的慢性肝病之一。迄今该病确切发病机制仍未阐明，也缺乏公认、有效的治疗方法。脂质介质Protectin DX（PDX）是二十二碳六烯酸（DHA）经过脂氧合酶催化作用合成的衍生物。我们的前期研究发现，高脂饮食小鼠予PDX干预后肝脏脂质沉积减轻，提示PDX对NAFLD具有保护作用。同时我们发现PDX干预后肝脏AMPK激活，已有研究证实AMPK的激活可通过多种信号途径改善NAFLD，故本项目拟开展以下工作：1、在不同的NAFLD小鼠模型中，明确PDX对肝脂肪变性及脂肪性肝炎形成的影响；2、通过体内外实验明确AMPK信号通路在PDX调控肝脏脂质代谢、炎症反应中的作用及机制；3、进一步明确AMPK-mTOR通路相关的细胞自噬在PDX调控NAFLD形成中的作用及分子机制。通过该项目希望能为NAFLD的药物干预治疗提供新思路。

非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）目前已成为全球范围内的主要慢性肝脏疾病类型并严重危害人类健康，其发病机制复杂，尚缺乏有效的临床治疗及干预手段。根据我们前期预实验结果，本项目围绕脂质介质Protectin DX（PDX）对NAFLD的保护作用及其作用机制，通过高脂饮食（high fat diet，HFD）以及蛋氨酸胆碱缺乏饮食（Methionine-choline-deficient diet，MCD）喂养，构建了NAFLD及非酒精性脂肪性肝炎（nonalcoholic steatohepatitis，NASH）动物模型，发现PDX可抑制肝脏脂质合成并增强脂肪酸β氧化从而减轻肝脏脂肪变性，同时可有效减少MCD小鼠肝巨噬细胞浸润、激活，改善肝脏炎症状态，减轻组织损伤。机制研究发现：PDX可通过减轻肝细胞内质网应激（Endoplasmic reticulum stress，ERS）、增强细胞自噬（autophagy），进而抑制NF-κB以及JNK信号通路激活改善肝细胞脂质代谢，减轻细胞炎症反应。此外，肝脏固有免疫在NASH的发生发展过程中发挥重要作用，本研究发现：PDX可减少棕榈酸（palmitic acid，PA）诱导的巨噬细胞活性氧（reactive oxygen species，ROS）生成，改善细胞氧化应激，促使其向产生抗炎作用的M2型极化，增加IL-10合成同时减少炎症介质（TNF-α、IL-6）的表达，从而改善细胞炎症状态，该作用可能同NLRP3炎性小体活化受抑制有关。综上，PDX可有效改善NAFLD，其未来可能成为该类疾病的潜在有效治疗药物。