Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung, South Korea.
Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea.
Front Endocrinol (Lausanne). 2022 Oct 4;13:934847. doi: 10.3389/fendo.2022.934847. eCollection 2022.
Despite the global prevalence of nonalcoholic fatty liver disease (NAFLD), its pathophysiology remains unclear. In this study, we established highly confident nonalcoholic steatohepatitis (NASH) gene signatures and evaluated the pathological mechanisms underlying NASH through a systematic meta-analysis of transcriptome and proteome datasets obtained from NASH patients and mouse models.
We analyzed NASH transcriptome datasets from 539 patients and 99 mice. A whole-liver tissue proteome dataset was used to confirm the protein level dysregulation of NASH signatures significant in both humans and mice.
In total, 254 human and 1,917 mouse NASH gene signatures were established. Up-regulated genes of 254 human signatures were associated with inflammation, steatosis, apoptosis, and extracellular matrix organization, whereas down-regulated genes were associated with response to metal ions and lipid and amino acid metabolism. When different mouse models were compared against humans, models with high fat and high fructose diet most closely resembled the genetic features of human NAFLD. Cross-species analysis revealed 66 genes that were concordantly dysregulated between human and mouse NASH. Among these, 14 genes were further validated to be dysregulated at the protein level. The resulting 14 genes included some of the well-established NASH associated genes and a promising NASH drug target. Functional enrichment analysis revealed that dysregulation of amino acid metabolism was the most significant hepatic perturbation in both human and mouse NASH.
We established the most comprehensive hepatic gene signatures for NASH in humans and mice to date. To the best of our knowledge, this is the first study to collectively analyze the common signatures between human and mouse NASH on a transcriptome-proteome scale.
尽管非酒精性脂肪性肝病 (NAFLD) 在全球范围内普遍存在，但它的病理生理学仍然不清楚。在这项研究中，我们建立了高度可信的非酒精性脂肪性肝炎 (NASH) 基因特征，并通过对来自 NASH 患者和小鼠模型的转录组和蛋白质组数据集进行系统的荟萃分析，评估了 NASH 的潜在病理机制。
我们分析了来自 539 名患者和 99 只小鼠的 NASH 转录组数据集。使用全肝组织蛋白质组数据集来确认在人类和小鼠中均显著失调的 NASH 特征的蛋白质水平失调。
总共建立了 254 个人类和 1917 个小鼠 NASH 基因特征。254 个人类特征的上调基因与炎症、脂肪变性、细胞凋亡和细胞外基质组织有关，而下调基因与对金属离子和脂质及氨基酸代谢的反应有关。当比较不同的小鼠模型与人类时，高脂肪和高果糖饮食的模型与人类 NAFLD 的遗传特征最为相似。跨物种分析揭示了 66 个在人类和小鼠 NASH 中均失调的基因。在这些基因中，有 14 个基因在蛋白质水平上进一步被验证为失调。由此产生的 14 个基因包括一些已确立的 NASH 相关基因和有前途的 NASH 药物靶点。功能富集分析显示，在人类和小鼠 NASH 中，氨基酸代谢失调是肝脏最显著的紊乱。
我们迄今为止在人类和小鼠中建立了最全面的 NASH 肝脏基因特征。据我们所知，这是第一项在转录组-蛋白质组范围内对人类和小鼠 NASH 的共同特征进行综合分析的研究。
