Cells (Sep 2021)
Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
- Ahmed Ghallab,
- Maiju Myllys,
- Adrian Friebel,
- Julia Duda,
- Karolina Edlund,
- Emina Halilbasic,
- Mihael Vucur,
- Zaynab Hobloss,
- Lisa Brackhagen,
- Brigitte Begher-Tibbe,
- Reham Hassan,
- Michael Burke,
- Erhan Genc,
- Lynn Johann Frohwein,
- Ute Hofmann,
- Christian H. Holland,
- Daniela González,
- Magdalena Keller,
- Abdel-latif Seddek,
- Tahany Abbas,
- Elsayed S. I. Mohammed,
- Andreas Teufel,
- Timo Itzel,
- Sarah Metzler,
- Rosemarie Marchan,
- Cristina Cadenas,
- Carsten Watzl,
- Michael A. Nitsche,
- Franziska Kappenberg,
- Tom Luedde,
- Thomas Longerich,
- Jörg Rahnenführer,
- Stefan Hoehme,
- Michael Trauner,
- Jan G. Hengstler
Affiliations
- Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Maiju Myllys
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Adrian Friebel
- Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstr. 16-18, 04107 Leipzig, Germany
- Julia Duda
- Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany
- Karolina Edlund
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Emina Halilbasic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
- Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty at Heinrich-Heine-University, University Hospital Duesseldorf, 40225 Dusseldorf, Germany
- Zaynab Hobloss
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Lisa Brackhagen
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Brigitte Begher-Tibbe
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Michael Burke
- MRI Unit, Leibniz Research Centre for Working Environment and Human Factors, Department of Psychology and Neurosciences, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Erhan Genc
- MRI Unit, Leibniz Research Centre for Working Environment and Human Factors, Department of Psychology and Neurosciences, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Lynn Johann Frohwein
- Siemens Healthcare GmbH, 91052 Erlangen, Germany
- Ute Hofmann
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Auerbachstr. 112, 70376 Stuttgart, Germany
- Christian H. Holland
- Institute of Computational Biomedicine, Heidelberg University, Faculty of Medicine, Bioquant—Im Neuenheimer Feld 267, 69120 Heidelberg, Germany
- Daniela González
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Magdalena Keller
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Abdel-latif Seddek
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
- Tahany Abbas
- Histology Department, Faculty of Medicine, South Valley University, Qena 83523, Egypt
- Elsayed S. I. Mohammed
- Department of Histology and Cytology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
- Andreas Teufel
- Department of Medicine I, University Hospital, 93053 Regensburg, Germany
- Timo Itzel
- Department of Medicine I, University Hospital, 93053 Regensburg, Germany
- Sarah Metzler
- Leibniz Research Centre for Working Environment and Human Factors, Department of Immunology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Rosemarie Marchan
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Cristina Cadenas
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Carsten Watzl
- Leibniz Research Centre for Working Environment and Human Factors, Department of Immunology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Michael A. Nitsche
- Leibniz Research Centre for Working Environment and Human Factors, Department of Psychology and Neurosciences, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- Franziska Kappenberg
- Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany
- Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty at Heinrich-Heine-University, University Hospital Duesseldorf, 40225 Dusseldorf, Germany
- Thomas Longerich
- Translational Gastrointestinal Pathology, Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany
- Jörg Rahnenführer
- Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany
- Stefan Hoehme
- Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstr. 16-18, 04107 Leipzig, Germany
- Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
- Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany
- DOI
- https://doi.org/10.3390/cells10102516
- Journal volume & issue
-
Vol. 10,
no. 10
p. 2516
Abstract
Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.
Keywords