期刊
CELLS
卷 10, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/cells10102516
关键词
NASH; non-invasive imaging; transcriptomics; intravital imaging
类别
资金
- German Research Foundation (DFG) [GH 276/1-1, 457840828]
- Federal Ministry of Education and Research (BMBF, Germany) [FKZ 031L0052]
- Austrian Science Foundation (FWF) [F7310]
- Research Training Group Biostatistical Methods for High-Dimensional Data in Toxicology - German Research Foundation (DFG) [RTG 2624, 427806116]
- BMBF LiSyM grant [FKZ 031L0037]
- Robert Bosch Stiftung, Stuttgart
In this study, time-resolved characterization of a mouse model of NAFLD identified a sequence of eight key events in the development of the disease, along with functional changes and transcriptomic landscape similarities to human NAFLD and HCC. The findings provide a basis for identifying therapeutic targets in NAFLD.
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.
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