A human liver chimeric mouse model for non-alcoholic fatty liver disease
Beatrice Bissig-Choisat,
Michele Alves-Bezerra,
Barry Zorman,
Scott A. Ochsner,
Mercedes Barzi,
Xavier Legras,
Diane Yang,
Malgorzata Borowiak,
Adam M. Dean,
Robert B. York,
N. Thao N. Galvan,
John Goss,
William R. Lagor,
David D. Moore,
David E. Cohen,
Neil J. McKenna,
Pavel Sumazin,
Karl-Dimiter Bissig
Affiliations
Beatrice Bissig-Choisat
Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA
Michele Alves-Bezerra
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
Barry Zorman
Texas Children’s Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Scott A. Ochsner
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Mercedes Barzi
Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA
Xavier Legras
Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA
Diane Yang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Malgorzata Borowiak
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Institute for Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz Universtiy, Poznan, Poland
Adam M. Dean
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Robert B. York
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
N. Thao N. Galvan
Department of Surgery, Texas Children’s Hospital, Houston, TX, USA
John Goss
Department of Surgery, Texas Children’s Hospital, Houston, TX, USA
William R. Lagor
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
David D. Moore
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
David E. Cohen
Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA
Neil J. McKenna
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Pavel Sumazin
Texas Children’s Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Karl-Dimiter Bissig
Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA; Y.T. and Alice Chen Pediatric Genetics and Genomics Research Center, Duke University, Durham, NC, USA; Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA; Duke Cancer Institute, Duke University, Durham, NC, USA; Corresponding author. Address: Duke University, Division of Medical Genetics, 905 South LaSalle street, Durham, NC-27708, USA. Tel.: +1 919 660 0761; fax: +1 919 660 0762.
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 Il2rg-/-/Rag2-/-/Fah-/-) 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.
