一种用于非酒精性脂肪性肝病的人肝嵌合小鼠模型。
A human liver chimeric mouse model for non-alcoholic fatty liver disease.
作者信息
Bissig-Choisat Beatrice, Alves-Bezerra Michele, Zorman Barry, Ochsner Scott A, Barzi Mercedes, Legras Xavier, Yang Diane, Borowiak Malgorzata, Dean Adam M, York Robert B, Galvan N Thao N, Goss John, Lagor William R, Moore David D, Cohen David E, McKenna Neil J, Sumazin Pavel, Bissig Karl-Dimiter
机构信息
Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
出版信息
JHEP Rep. 2021 Mar 21;3(3):100281. doi: 10.1016/j.jhepr.2021.100281. eCollection 2021 Jun.
BACKGROUND & AIMS: The accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world's population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despite insights gained from both human and animal studies, our understanding of NAFLD pathogenesis remains limited. To better study the molecular changes driving the condition we aimed to generate a humanised NAFLD mouse model.
METHODS
We generated TIRF (transgene-free / / ) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks.
RESULTS
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.
CONCLUSIONS
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.
LAY SUMMARY
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.
背景与目的
肝细胞内中性脂质的积累是非酒精性脂肪性肝病（NAFLD）的基础，该疾病影响着全球四分之一的人口，并与肝炎、肝硬化和肝细胞癌相关。尽管从人类和动物研究中获得了一些见解，但我们对NAFLD发病机制的理解仍然有限。为了更好地研究导致该疾病的分子变化，我们旨在建立一种人源化的NAFLD小鼠模型。
方法
我们培育了无转基因（TIRF）小鼠，将人肝细胞植入其肝脏，并给予它们西式饮食12周。
结果
在同一嵌合肝脏中，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。转录组分析表明，鼠肝细胞和人肝细胞之间的分子反应存在显著差异，这表明肝功能存在明显的物种差异。调控网络分析表明，我们的模型与临床NAFLD在胆固醇生物合成的转录控制方面密切一致。
结论
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，并为研究脂肪变性引起的致病变化提供了一个生理相关、易于实验操作的模型。
简要概述
脂肪性肝病是一个新出现的健康问题，由于没有良好的实验动物模型，我们对该疾病的了解很少。我们在此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比较。结果显示，小鼠肝脏中的人细胞在西式高脂肪饮食后会发生脂肪性肝病，而小鼠细胞看起来正常。人细胞的分子特征（表达谱）与小鼠细胞不同，对人源化肝脏的代谢分析模拟了在患有脂肪性肝病的人类中观察到的情况。这种新型的人源化小鼠系统可用于研究人类脂肪性肝病。
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