Non-alcoholic fatty liver disease (NAFLD) can manifest as non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). NASH is often associated with progressive fibrosis which can lead to cirrhosis and hepatocellular carcinoma (HCC). NASH is increasing as an aetiology for end-stage liver disease as well as HCC. There are currently no approved therapies for NASH. A major barrier to development of therapeutics for NASH is the lack of preclinical models of disease that are appropriately validated to represent the biology and outcomes of human disease. Many in vitro and animal models have been developed. In vitro models do not fully capture the hepatic and extrahepatic milieu of human NASH and large animal models are expensive and logistically difficult to use. Therefore, there is considerable interest in the development and validation of mouse models for NAFLD, including NASH. Several models based on varying genetic or dietary manipulations have been developed. However, the majority do not recreate steatohepatitis, strictly defined as the presence of hepatocellular ballooning with or without Mallory-Denk bodies, accompanied by inflammation in the presence of macrovesicular steatosis. Others lack validation against human disease. Herein, we describe the best practices in development of mouse models of NASH. We further review existing models and the literature supporting their use as a surrogate for human disease. Finally, data on models to evaluate protective genes are discussed. It is hoped that this review will provide guidance for the interpretation of data derived from mouse models and also for the development and validation of newer models.

中文翻译：

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非酒精性脂肪肝的临床前模型

非酒精性脂肪肝 (NAFLD) 可表现为非酒精性脂肪肝 (NAFL) 或非酒精性脂肪性肝炎 (NASH)。NASH 通常与进行性纤维化有关，后者可导致肝硬化和肝细胞癌 (HCC)。NASH 作为终末期肝病和 HCC 的病因正在增加。目前没有批准的 NASH 疗法。开发 NASH 疗法的一个主要障碍是缺乏经过适当验证以代表人类疾病生物学和结果的疾病临床前模型。已经开发了许多体外和动物模型。体外模型不能完全捕捉人类 NASH 的肝脏和肝外环境，大型动物模型价格昂贵且逻辑上难以使用。所以，人们对 NAFLD 小鼠模型的开发和验证非常感兴趣，包括 NASH。已经开发了几种基于不同遗传或饮食操作的模型。然而，大多数不会重现脂肪性肝炎，严格定义为存在或不存在 Mallory-Denk 小体的肝细胞气球样变，伴有大泡性脂肪变性的炎症。其他人缺乏针对人类疾病的验证。在此，我们描述了 NASH 小鼠模型开发的最佳实践。我们进一步审查了现有模型和支持它们作为人类疾病替代品的文献。最后，讨论了评估保护基因的模型数据。