{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:19:13Z","timestamp":1790533153890,"version":"4.1.0"},"reference-count":68,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T00:00:00Z","timestamp":1632355200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GH 276\/1-1; project no. 457840828"],"award-info":[{"award-number":["GH 276\/1-1; project no. 457840828"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RTG 2624 \u201dBiostatistical Methods for High-Dimensional Data in Toxicology"],"award-info":[{"award-number":["RTG 2624 \u201dBiostatistical Methods for High-Dimensional Data in Toxicology"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["the Liver-LiSyM grant FKZ 031L0052"],"award-info":[{"award-number":["the Liver-LiSyM grant FKZ 031L0052"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["LiSyM grant FKZ 031L0037"],"award-info":[{"award-number":["LiSyM grant FKZ 031L0037"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Robert Bosch Stiftung, Stuttgart","award":["Stuttgart"],"award-info":[{"award-number":["Stuttgart"]}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["F7310"],"award-info":[{"award-number":["F7310"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 \u2018rest-and-jump genes\u2019 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\u201348. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.<\/jats:p>","DOI":"10.3390\/cells10102516","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T09:59:15Z","timestamp":1632391155000},"page":"2516","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0695-3403","authenticated-orcid":false,"given":"Ahmed","family":"Ghallab","sequence":"first","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"},{"name":"Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9117-4572","authenticated-orcid":false,"given":"Maiju","family":"Myllys","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Friebel","sequence":"additional","affiliation":[{"name":"Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstr. 16-18, 04107 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3894-0124","authenticated-orcid":false,"given":"Julia","family":"Duda","sequence":"additional","affiliation":[{"name":"Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2143","authenticated-orcid":false,"given":"Karolina","family":"Edlund","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4878-1470","authenticated-orcid":false,"given":"Emina","family":"Halilbasic","sequence":"additional","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihael","family":"Vucur","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty at Heinrich-Heine-University, University Hospital Duesseldorf, 40225 Dusseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaynab","family":"Hobloss","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Brackhagen","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Begher-Tibbe","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6569-7676","authenticated-orcid":false,"given":"Reham","family":"Hassan","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"},{"name":"Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8516-9889","authenticated-orcid":false,"given":"Michael","family":"Burke","sequence":"additional","affiliation":[{"name":"MRI Unit, Leibniz Research Centre for Working Environment and Human Factors, Department of Psychology and Neurosciences, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3060-5786","authenticated-orcid":false,"given":"Christian H.","family":"Holland","sequence":"additional","affiliation":[{"name":"Institute of Computational Biomedicine, Heidelberg University, Faculty of Medicine, Bioquant\u2014Im Neuenheimer Feld 267, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Keller","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, 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