非酒精性脂肪肝病的驱动因素及临床试验药物研究进展

Driving Factors of Non-alcoholic Fatty Liver Disease and Research Progress of Clinical Trial Drugs

伴随着生活方式和饮食水平的重大转变,非酒精性脂肪肝病(Non-alcoholic fatty liver disease,NAFLD)的全球患病率已由2015年的25%升高至29.8%,NAFLD已成为全球最常见的慢性肝病。NAFLD依据组织学特征可分为非酒精性脂肪肝(Non-alcoholic fatty liver,NAFL)和非酒精性脂肪肝炎(Non-alcoholic steatohepatitis,NASH)两个阶段,后者在脂肪变性的基础上伴有肝细胞损伤、气球样病变和小叶炎症。慢性炎症通常可诱导纤维化的发生,甚至进展为肝硬化和肝细胞癌,造成肝脏功能衰竭和死亡。目前根据不同阶段主要驱动因素的不同已发掘出众多的药物治疗靶点并进行了相应的临床试验。其中,NAFL的主要驱动因素是饮食造成的脂代谢失调和胰岛素抵抗,因此针对脂代谢相关酶类活性调节或增强胰岛素敏感性是改善肝脏脂肪变性的主要研究方向。NASH的发生与多种因素相关,包括脂毒性和细胞死亡、氧化应激和线粒体功能障碍以及肝脏外的脂肪组织炎症和肠道屏障功能障碍等,针对这些途径也都进行了相应的药物开发和临床试验。尽管针对NAFLD的临床药物开发不断取得进展,但目前仅有印度药品监督管理局在2020年3月批准过氧化物酶体增殖物激活受体α/γ(Peroxisome proliferator activated receptor,PPARα/γ)双重激动剂Saroglitazar用于治疗非肝硬化型NASH患者,这也是世界上首个获批的NASH治疗药物,其疗效还有待进一步观察。本综述通过对NAFL和NASH的主要驱动因素进行梳理和分类,并对各治疗靶点相应的正在进行临床试验的药物做简要介绍,希望能有助于NAFLD发病机制研究和药物开发。

Concomitant with major changes in lifestyle and diet,the global prevalence of non-alcoholic fatty liver disease(NAFLD)has increased from 25%in 2015 to 29.8%,NAFLD has become the most common chronic liver disease worldwide.Based on histological characteristics,NAFLD can be divided into two stages:non-alcoholic fatty liver(NAFL)and non-alcoholic steatohepatitis(NASH).On the basis of steatosis,NASH is accompanied with hepatocyte injury,ballooning lesions and lobular inflammation.Chronic inflammation can usually induce fibrosis,even progress to cirrhosis and hepatocellular carcinoma,resulting in liver failure and death.At present,according to the main driving factors of different stages,many drug therapeutic targets have been discovered and corresponding clinical trials conducted.Among them,the main driving factors of NAFL are diet induced dysregulation of lipid metabolism and insulin resistance.Therefore,regulating the activities of lipid metabolism related enzymes or enhancing insulin sensitivity is the main research direction to ameliorate hepatic steatosis.The occurrence of NASH is associated with a variety of factors,including lipotoxicity and cell death,oxidative stress and mitochondrial dysfunction,as well as adipose tissue inflammation and impaired intestinal barrier function.Corresponding drug development and clinical trials have also been conducted targeting these pathways.Although the clinical drug development for NAFLD has made continuous progress,only Saroglitazar,a peroxisome proliferator activated receptorα/γdouble agonist,was approved by the Indian Drug Administration in March 2020 for the treatment of non-cirrhotic NASH patients.This is the first approved NASH therapeutic drug in the world,but its efficacy remains to be further observed.This review sorts out and classifies the main driving factors of NAFL and NASH,and briefly introduces the drugs under clinical trials corresponding to each therapeutic target,hoping to contribute to the research on the pathogenesis of NAFLD and drug development.