Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments.
Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments.
复制标题
非酒精性脂肪性肝炎：对其机制，模型和医疗治疗的回顾。
DOI：
10.3389/fphar.2020.603926
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发表时间：
2020
影响因子：
5.6
通讯作者：
Qin CX
中科院分区：
文献类型：
--
作者：
Peng C;Stewart AG;Woodman OL;Ritchie RH;Qin CX
非酒精性脂肪性肝炎（NASH）是由非酒精性脂肪性肝病（NAFLD）发展而来的。目前，估计约25%的人口患有NAFLD，估计25%的NAFLD患者患有NASH。NASH的典型特征在于肝脏脂肪变性炎症，以及由代谢破坏（例如肥胖、糖尿病和血脂异常）驱动的纤维化。具有显著纤维化的NASH患者发展为肝硬化和肝衰竭的风险增加。目前，NASH是美国肝移植的第二大原因。更重要的是，NASH发展为肝细胞癌的风险在最近的研究中也得到了强调。患者在进展为NASH之前可能患有NAFLD多年。虽然NASH的发病机制尚未完全了解，但目前的“多次打击”假说表明，除了脂肪积累外，氧化和ER应激的升高也可能导致肝脏炎症和纤维化。NASH的临床相关动物模型和药物治疗的开发受到对疾病机制的有限理解和缺乏敏感的非侵入性诊断工具的阻碍。目前，临床前动物模型主要分为三大类：遗传模型、饮食诱导模型和毒素+饮食诱导模型。尽管饮食模型模拟了人类NASH的自然过程，但这些模型通常仅诱导轻度肝损伤。许多遗传和毒素+饮食诱导的模型迅速诱导代谢紊乱和严重肝损伤的发展，但并非没有其自身的缺点。本文综述了“多次打击”假说的概述和对目前现有NASH动物模型的评价。该综述还提供了关于管理NASH的可用干预措施以及目前正在进行NASH治疗临床试验的药理学药物的最新信息。
Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.