Boeckmans Joost, Natale Alessandra, Buyl Karolien, Rogiers Vera, De Kock Joery, Vanhaecke Tamara, Rodrigues Robim M
Department of In VitroToxicology & Dermato-Cosmetology (IVTD) Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Pharmacol Res. 2018 Aug;134:257-267. doi: 10.1016/j.phrs.2018.06.029. Epub 2018 Jun 30.
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by excessive triglyceride accumulation in the liver accompanied by inflammation, cell stress and apoptosis. It is the tipping point to the life-threatening stages of non-alcoholic fatty liver disease (NAFLD). Despite the high prevalence of NASH, up to five percent of the global population, there are currently no approved drugs to treat this disease. Animal models, mostly based on specific diets and genetic modifications, are often employed in anti-NASH drug development. However, due to interspecies differences and artificial pathogenic conditions, they do not represent the human situation accurately and are inadequate for testing the efficacy and safety of potential new drugs. Human-based in vitro models provide a more legitimate representation of the human NASH pathophysiology and can be used to investigate the dysregulation of cellular functions associated with the disease. Also in silico methodologies and pathway-based approaches using human datasets, may contribute to a more accurate representation of NASH, thereby facilitating the quest for new anti-NASH drugs. In this review, we describe the molecular components of NASH and how human-based tools can contribute to unraveling the pathogenesis of this disease and be used in anti-NASH drug development. We also propose a roadmap for the development and application of human-based approaches for future investigation of NASH.
非酒精性脂肪性肝炎（NASH）是一种慢性肝病，其特征是肝脏中甘油三酯过度积累，并伴有炎症、细胞应激和细胞凋亡。它是非酒精性脂肪性肝病（NAFLD）危及生命阶段的转折点。尽管NASH在全球高达5%的人口中具有很高的患病率，但目前尚无获批用于治疗该疾病的药物。抗NASH药物研发中常采用动物模型，这些模型大多基于特定饮食和基因改造。然而，由于种间差异和人为致病条件，它们不能准确代表人类情况，不足以测试潜在新药的疗效和安全性。基于人类的体外模型能更合理地反映人类NASH的病理生理学，可用于研究与该疾病相关的细胞功能失调。此外，使用人类数据集的计算机方法和基于通路的方法，可能有助于更准确地呈现NASH，从而促进新型抗NASH药物的研发。在本综述中，我们描述了NASH的分子成分，以及基于人类的工具如何有助于揭示该疾病的发病机制，并用于抗NASH药物研发。我们还为基于人类的方法在未来NASH研究中的开发和应用提出了路线图。
