摘要
非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)是代谢相关性脂肪肝病(metabolic associatedfattyliverdisease,MAFLD)肝脏特征性病理表现,是MAFLD从相对良性和可逆阶段向肝损伤甚至肝硬化和肝细胞癌发展的关键转折点。近年来研究表明,脂质沉积和氧化应激贯穿于MAFLD始终,而改善肝脂肪沉积和氧化应激是目前治疗和预防NASH疾病发生和发展的主要干预途径。一般来说,促进自噬水平可减少脂质积累(triglyceride,TG)和氧化应激(oxidative stress,OS)并促进肝细胞存活,而阻断自噬水平可能会加速NASH的进展。但自噬水平的激活与上游信号AMPK/mTOR/ULK1的活化及EI24的调控密不可分。其中一种与AMPK、mTOR通道活化密切相关的自噬跨膜蛋白依托泊苷诱导2.4蛋白(Etoposide-induced protein 2.4,EI24),可通过促进自噬溶酶体的降解加速自噬流的活化过程。同时,间充质干细胞(mesenchymal stem cells,MSCs)作为理想的自噬诱导体,凭借其激活AMPK/mTOR介导性自噬在治疗各种NASH炎症性疾病方面优异的治疗效果被广泛研究。因此,当采用MSCs以“药物作用”调控EI24/AMPK/mTOR轴促进自噬改善或逆转NASH脂肪堆积、氧化应激等肝损伤,以期为NASH相关发病机制的阐明和开发新的治疗策略提供依据。
NASH is the characteristic pathological manifestation of the liver in MAFLD,which is a key turning point in the development of MAFLD from a relatively benign and reversible stage to liver injury and even cirrhosis and hepatocellular carcinoma.Recent studies have shown that lipid deposition and oxidative stress run through MAFLD metabolic diseases,and improving hepatic lipid deposition and oxidative stress is the main intervention approach for the treatment and prevention of NASH disease.In general,promoting autophagy levels can reduce triglyceride(TG)accumulation and oxidative stress(OS)and promote hepatocyte survival,while blocking autophagy levels may accelerate the progression of NASH.However,the activation of autophagy levels is closely related to the activation of upstream signals AMPK/mTOR/ULK1 and the regulation of EI24.EI24,an essential autophagy protein closely related to the activation of AMPK and mTOR protein channels,can accelerate the activation of autophagy flow by promoting the degradation process of autophagy-lysosome.Meanwhile,mesenchymal stem cells(MSCs)as ideal autophagy inducers have been widely studied for their excellent therapeutic effects in treating various inflammatory diseases such as NAFLD through the activation of AMPK/mTOR-mediated autophagy.Therefore,“drug-acting”mesenchymal stem cells should be used to regulate the activation of autophagy level of EI24/AMPK/mTOR to promote autophagy,inhibit adipogenesis and reduce lipid deposition,and effectively alleviate or reverse NASH liver injury,to provide a basis for elucidating the pathogenesis of NASH related diseases and developing new therapeutic strategies.
作者
梁晨晨
高建鹏
LIANG Chenchen;GAO Jianpeng(School of Public Health,Dali University,Dali Yunnan 671013;Administration Section,Yan’an Hospital,Kunming Yunnan 650041,China)
出处
《昆明医科大学学报》
CAS
2023年第7期162-167,共6页
Journal of Kunming Medical University
基金
国家自然科学基金资助项目(81860424)
深圳市科技攻关项目(202247)。
