非酒精性脂肪性肝病(NAFLD)是世界范围内慢性肝病的一个主要原因,约15%的NAFLD患者会发展为非酒精性脂肪性肝炎、肝纤维化、肝硬化甚至肝癌。目前其发病及进展机制尚未明确,也无有效治疗手段。因此,构建临床前NAFLD动物模型至关重要,有助于为NAFLD提供临床治疗的新方案。本文将系统分析目前已构建的NAFLD动物模型在临床前研究中的局限性,并重点总结和综述基于基因编辑在NAFLD动物模型构建中的应用及研究进展,这对于探讨NAFLD发病机制及新药研发具有重要的临床意义。

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, and about 15% of NAFLD patients will develop into nonalcoholic steatohepatitis, hepatic fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. However, the biological mechanism of the pathogenesis and progression of NAFLD is not fully understood, and there are still no effective or targeted therapies for NAFLD. Therefore, it is an urgent need to construct pre-clinical animal models of NAFLD, which will help to better understand and explore the potential therapeutic strategy in the treatment of NAFLD. Here, we summarize the recent advances and limitations of the established animal models of NAFLD and focus on the potential application and research progress of genome editing for constructing the animal models of NAFLD. There animal models will be very useful to reveal the pathologic mechanism of human NAFLD, and to screen new therapeutic drugs.

目的 通过生物信息分析途径,从分子水平揭示非酒精性脂肪性肝病（NAFLD）的发病发展机制,为NAFLD研究提供新的思路。方法 从公共数据库GEO中下载NAFLD相关的基因芯片数据GSE48452,利用Transcriptome Analysis Console软件筛选差异表达基因,FunRich软件和STRING在线分析工具对差异基因进行下一步的生物信息学分析。结果 正常组与NAFLD组差异基因52个,正常组与非酒精性脂肪性肝炎（NASH）基因64个,共同差异基因15个。这些差异表达基因参与脂质转运、胆汁酸合成、脂质和脂蛋白代谢、生物氧化等过程。通过通路分析及蛋白质相互作用分析进一步筛选出与NAFLD发病发展密切相关的18个差异表达基因。结论 通过生物信息学分析筛选出MSN、CDC45、ANXA5、PIK3CG和DTL基因可能为研究乃至阻断NAFLD发展进程的重要靶点,需进一步验证。

Objective To explore the molecular mechanism of nonalcoholic fatty liver disease （NAFLD） with bioinformatics analysis. Methods The microarray data of NAFLD were downloaded from the Gene Expression Omnibus （GEO） database and analyzed using Transcriptome Analysis Console （TAC） for screening differentially expressed genes. The further analysis of differentially expressed genes was conducted by FunRich software and the online tool STRING. Results For the comparison of control group vs. NAFLD group,52 genes have differentially expressed,while control groups vs. nonalcoholic steatohepatitis （NASH） group,64 genes have differentially expressed. 15 differentially expressed genes were found in both comparisons. These genes were involved in the biological pathway of lipid transport,bile acid biosynthesis,metabolism of lipids and lipoproteins and biological oxidations. With biological pathway analysis and protein-protein interaction analysis,18 differentially expressed genes were found closely associated with the progression of NAFLD. Conclusion MSN、CDC45、ANXA5、PIK3CG and DTL may be the important target for study the progression of NAFLD,which needs a further study to confirm.