UNASSIGNED: We generated TIRF (transgene-free Il2rg -/-/Rag2 -/-/Fah -/-) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks.
UNASSIGNED: Within the same chimeric liver, human hepatocytes developed pronounced steatosis whereas murine hepatocytes remained normal. Unbiased metabolomics and lipidomics revealed signatures of clinical NAFLD. Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes, demonstrating stark species differences in liver function. Regulatory network analysis indicated close agreement between our model and clinical NAFLD with respect to transcriptional control of cholesterol biosynthesis.
UNASSIGNED: These NAFLD xenograft mice reveal an unexpected degree of evolutionary divergence in food metabolism and offer a physiologically relevant, experimentally tractable model for studying the pathogenic changes invoked by steatosis.
UNASSIGNED: Fatty liver disease is an emerging health problem, and as there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanised mouse system and compare it with clinical data. The results reveal that the human cells in the mouse liver develop fatty liver disease upon a Western-style fatty diet, whereas the mouse cells appear normal. The molecular signature (expression profiles) of the human cells are distinct from the mouse cells and metabolic analysis of the humanised livers mimic the ones observed in humans with fatty liver. This novel humanised mouse system can be used to study human fatty liver disease.
■我们产生了TIRF(无转基因的Il2rg-/-/Rag2-/-/Fah-/-)小鼠,他们的肝脏充满了人类肝细胞,给他们吃了12周的西式饮食。
■在同一个嵌合肝脏中,人肝细胞出现明显的脂肪变性,而鼠肝细胞保持正常。无偏代谢组学和脂质组学揭示了临床NAFLD的特征。转录组学分析显示,分子反应在鼠和人肝细胞之间急剧分歧,显示肝脏功能的明显物种差异。调控网络分析表明,在胆固醇生物合成的转录控制方面,我们的模型与临床NAFLD密切相关。
■这些NAFLD异种移植小鼠揭示了食物代谢中意想不到的进化差异程度,用于研究脂肪变性引起的致病性变化的实验可处理模型。
■脂肪肝是一种新兴的健康问题,因为没有好的实验动物模型,我们对这种情况的理解很差。我们在这里描述了一种新型的人源化小鼠系统,并将其与临床数据进行了比较。结果表明,在西式脂肪饮食下,小鼠肝脏中的人类细胞会发展为脂肪肝疾病,而小鼠细胞看起来正常。人细胞的分子特征(表达谱)不同于小鼠细胞,并且人源化肝脏的代谢分析模拟在患有脂肪肝的人中观察到的那些。这种新型的人源化小鼠系统可用于研究人类脂肪肝疾病。