A human liver chimeric mouse model for non-alcoholic fatty liver disease

Abstract Background and 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 humanized NAFLD mouse model. Methods We generated TIRF (Transgene-free Il2rg-/-/Rag2-/-/Fah-/-) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for twelve weeks. Results Within the same chimeric liver, human hepatocytes developed pronounced steatosis while 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. Conclusion 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 since there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanized mouse system and compare it to clinical data. The results reveal that the human cells in the mouse liver develop a fatty liver disease upon a Western-style fatty diet, while 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 humanized livers mimic the ones observed in humans with fatty liver. This novel humanized mouse system can be used to study human fatty liver disease.