非酒精性脂肪肝小鼠和人类的肝脏转录组特征

摘要(中文译文)

非酒精性脂肪性肝病（NAFLD）是肝硬化和肝细胞癌的主要原因。作为NAFLD的起始阶段，非酒精性脂肪肝（NAFL）的治疗正受到越来越多的关注。高脂饮食（HFD）喂养的小鼠和遗传性瘦素缺乏（ob/ob）小鼠是重要的NAFL动物模型。然而，这些小鼠模型与人类NAFL的比较仍不清楚。在本研究中，采用HFD喂养小鼠和ob/ob小鼠作为NAFL动物模型。比较了肝脏组织病理学特征，并通过RNA测序（RNA-seq）对两种小鼠模型的肝脏转录组进行了分析。从GEO数据库下载了NAFL患者肝脏的RNA-seq数据。进一步利用功能富集分析和京都基因与基因组百科全书（KEGG）通路分析了肝脏中的全局基因表达谱。我们的结果表明，两种小鼠模型与人类NAFL的生化指标相似。与HFD喂养小鼠相比，ob/ob小鼠在组织学外观上与NAFL患者更为相似。小鼠和人类的肝脏转录组特征部分重叠。此外，在NAFL通路中，大多数基因在小鼠和人类中表现出相似的趋势，从而表明考虑到差异，这两种小鼠均可作为NAFL基础研究的模型。我们的研究结果表明，HFD喂养小鼠和ob/ob小鼠可在病理生理过程中部分模拟人类NAFL。本文对小鼠模型和人类NAFL肝脏转录组谱的比较分析，为理解这些NAFL模型的分子特征提供了见解。

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the main reason for cirrhosis and hepatocellular carcinoma. As a starting point for NAFLD, the treatment of nonalcoholic fatty liver (NAFL) is receiving increasing attention. Mice fed a high-fat diet (HFD) and hereditary leptin deficiency (ob/ob) mice are important NAFL animal models. However, the comparison of these mouse models with human NAFL is still unclear. In this study, HFD-fed mice and ob/ob mice were used as NAFL animal models. Liver histopathological characteristics were compared, and liver transcriptome from both mouse models was performed using RNA sequencing (RNA-seq). RNA-seq data obtained from the livers of NAFL patients was downloaded from the GEO database. Global gene expression profiles in the livers were further analyzed using functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Our results showed that the biochemical parameters of both mouse models and human NAFL were similar. Compared with HFD-fed mice, ob/ob mice were more similar in histologic appearance to NAFL patients. The liver transcriptome characteristics partly overlapped in mice and humans. Furthermore, in the NAFL pathway, most genes showed similar trends in mice and humans, thus demonstrating that both types of mice can be used as models for basic research on NAFL, considering the differences. Our findings show that HFD-fed mice and ob/ob mice can mimic human NAFL partly in pathophysiological process. The comparative analysis of liver transcriptome profile in mouse models and human NAFL presented here provides insights into the molecular characteristics across these NAFL models.

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