ω-3 PUFA缓解内质网应激干预NAFLD肝细胞损伤作用机制

NAFLD is a nutrition-related metabolic disease and showing the tendency of globalization. It was recently found that ω-3 PUFA has a positive intervention effect being capable of alleviating NAFLD by improving the balance of hepatic lipid metabolism and reducing liver cell damage significantly. However, the underlying mechanism is still unclear. Previous studies showed that sustained ERS plays a critical role in inducing cell damage and the subsequent development of NAFLD. Moreover, it was also found that ω-3 PUFA could regulate endoplasmic reticulum function and ERS significantly. Based on those previous findings, we hypothesize that ω-3 PUFA could intervene NAFLD disease progression by inhibiting inflammatory response and apoptosis via relieving ERS signals and regulating lipid metabolism. This project will investigate the relationship between the protective effect of ω-3 PUFA on liver cells of NAFLD and the different ERS signals at molecular, cellular and the whole system level. Meanwhile the mechanism by which ω-3 PUFA alleviates ERS will also be explored. Furthermore, the project will examine the specific ERS signaling pathways influenced by ω-3 PUFA to improve lipid metabolism, inhibit the expression of inflammatory factors including CREBH, NF-κB, JNK and CHOP, and decrease apoptosis. Elucidating the protective mechanism of ω-3 PUFA on hepatocytes under NAFLD will lay scientific foundation for the usage of ω-3 PUFA.

NAFLD是营养相关的代谢性疾病，呈全球化扩展趋势。近来发现ω-3 PUFA对NAFLD有正向干预作用，可改善肝脂代谢，降低肝细胞损伤，从而延缓疾病发展，但其机制尚不清楚。研究证实：持续的ERS是诱发细胞损伤导致NAFLD进展的重要机制，而ω-3 PUFA对内质网功能及ERS存在显著调节作用。据此提出：NAFLD条件下，ω-3 PUFA可通过缓解肝细胞持续的ERS，并通过ERS信号通路调节脂质代谢、抑制炎性反应和细胞凋亡，干预疾病进展。项目拟从分子、细胞及整体水平研究ω-3 PUFA对NAFLD肝细胞保护作用与ERS各信号通路的关系，探讨ω-3 PUFA缓解ERS的可能途径与机制。阐明ω-3 PUFA调节ERS特定信号通路，改善脂质代谢，抑制CREBH、NF-κB、JNK、CHOP等介导的炎性和/或凋亡途径，阻止细胞损伤的作用机制。为科学应用ω-3 PUFA干预NAFLD奠定理论基础。

非酒精性脂肪肝（NAFLD）是营养相关的代谢性疾病，呈全球化扩展趋势，目前并无有效的治疗药物。近来发现ω-3 PUFA对NAFLD有正向干预作用，可改善肝脂代谢，降低肝细胞损伤，从而延缓疾病发展，但其机制尚不清楚。我们提出：NAFLD高脂条件下，ω-3 PUFA通过改变内质网膜的组成、调节钙平衡或改善氧化状态，调节内质网功能，缓解高脂负荷诱导的持续内质网应激（ERS），通过ERS特定信号通路，改善脂质代谢，抑制CREBH、NF-κB、JNK、CHOP等介导的炎性反应和/或凋亡途径，阻止细胞损伤，干预NAFLD病程进展。项目从分子、细胞及动物整体水平开展，研究阐明了ω-3 PUFA干预作用与机制，揭示：ω-3 PUFA干预可全面缓解NAFLD肝组织中的内质网应激、氧化应激，并通过相关应激途径抑制肝组织中炎性因子及炎性信号分子的表达，缓解NAFLD疾病进展中关键的炎性应激，干预疾病的进展。ω-3 PUFA干预缓解内质网应激、炎性应激的主要机制：①通过改善膜脂组成，调节胞内Ca2+平衡与改善线粒体功能等机制，缓解内质网应激；②通过抑制LOX-1，可缓解内质网应激，及相关的JNK/AP-1途径炎性途径；③诱导巨噬细胞促进M2极化，直接或间接抑制M1极化，从而改变分泌的细胞因子组成，抑制炎性应激与炎性损伤；④控制肠道微生物革兰氏阴性菌的过度繁殖，缓解LPS激活的炎症反应。此外，新发现ω-3 PUFA通过调节一系列microRNA表达，影响肝脏与节律调节有关的基因表达，缓解高脂饮食引起的肝脏节律紊乱。研究为科学应用ω-3 PUFA干预NAFLD奠定理论基础。