脂肪肝疾病进展为非酒精性脂肪性肝炎(NASH)是人类死亡的主要原因。生活方式和环境化学暴露会增加人类对NASH的易感性。在人类中,尿液中双酚A(BPA)的存在与脂肪肝疾病相关,但祖先BPA暴露是否导致未暴露后代中人类NAFLD-NASH相关基因的激活尚不清楚.在这项研究中,使用田高鱼作为人类NAFLD的动物模型,我们研究了人类NAFLD-NASH的转录特征及其在未直接暴露的鱼类肝脏发病机理中的相关作用,但是他们的祖先在三代前的胚胎和围产期发育过程中暴露于BPA。BPA谱系男性和女性medaka中肝脏的大量RNA-Seq数据与公开可用的人类NAFLD-NASH患者数据的比较揭示了medaka肝脏中人类NAFLD-NASH转录特征的跨代改变。在人类NAFLD患者和medaka中,20%的差异表达基因(DEGs)被上调。特别是在女性中,在BPA谱系鱼和NAFLD患者组的肝脏中,27.69%下调,20%上调。在所有的DEG中,在祖先的BPA谱系女性中发现了52.31%的DEGs,这表明女性的NAFLD共享大多数人类NAFLD基因网络。路径分析显示β氧化,脂蛋白代谢,和HDL/LDL介导的转运过程与BPA谱系男性和女性中下调的DEG相关。相比之下,仅在BPA谱系雌性的肝脏中,编码脂肪生成相关蛋白的基因的表达显着升高。表现出myc激活的BPA谱系雌性,atf4,xbp1,stat4,和癌变途径,以及igf1的失活,提示其可能与晚期NAFLD表型相关。目前的结果表明,在medaka中参与人类NAFLD和跨代NAFLD进展的基因网络是保守的,并且medaka可以是了解肝脏疾病的发展和进展以及肝脏中的环境影响的极好的动物模型。
The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using
medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish that were not directly exposed, but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female
medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in
medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and
medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% were downregulated, and 20% were upregulated. Of all DEGs, 52.31% of DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared the majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that
medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.