Ghallab, Ahmed and Myllys, Maiju and Friebel, Adrian and Duda, Julia and Edlund, Karolina and Halilbasic, Emina and Vucur, Mihael and Hobloss, Zaynab and Brackhagen, Lisa and Begher-Tibbe, Brigitte and Hassan, Reham and Burke, Michael and Genc, Erhan and Frohwein, Lynn Johann and Hofmann, Ute and Holland, Christian H. and Gonzalez, Daniela and Keller, Magdalena and Seddek, Abdel-latif and Abbas, Tahany and Mohammed, Elsayed S. I. and Teufel, Andreas and Itzel, Timo and Metzler, Sarah and Marchan, Rosemarie and Cadenas, Cristina and Watzl, Carsten and Nitsche, Michael A. and Kappenberg, Franziska and Luedde, Tom and Longerich, Thomas and Rahnenfuehrer, Joerg and Hoehme, Stefan and Trauner, Michael and Hengstler, Jan G. (2021) Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression. CELLS, 10 (10): 2516. ISSN , 2073-4409
Full text not available from this repository. (Request a copy)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.</p>
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; MOUSE MODELS; QUANTIFICATION; AMMONIA; INJURY; CELLS; NASH; non-invasive imaging; transcriptomics; intravital imaging |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2022 09:48 |
| Last Modified: | 04 Oct 2022 09:48 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48223 |
Actions (login required)
 |
View Item |
