Hui, S.T., Kurt, Z. orcid.org/0000-0003-3186-8091, Tuominen, I. et al. (17 more authors)
(2018)
The genetic architecture of diet‐induced hepatic fibrosis in mice.
Hepatology, 68 (6).
pp. 2182-2196.
ISSN 0270-9139
Abstract
We report the genetic analysis of a “humanized” hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human apolipoprotein E*3‐Leiden and cholesteryl ester transfer protein and fed a “Western” diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors are involved. Moreover, genome‐wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. Conclusion: The pathways showed substantial overlap between our mouse model and the human disease.
Metadata
Item Type: | Article |
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Authors/Creators: | This paper has 20 authors. You can scroll the list below to see them all or them all.
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Copyright, Publisher and Additional Information: | © 2018 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, (http://creativecommons.org/licenses/by-nc/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
Keywords: | Amino Acids; Animals; Apolipoprotein E3; Cholesterol; Cholesterol Ester Transfer Proteins; Dietary Fats; Disease Models, Animal; Fatty Acids; Female; Gene Expression Profiling; Genome-Wide Association Study; Humans; Hyperlipidemias; Liver; Liver Cirrhosis; Male; Mice, Inbred C57BL; Mice, Transgenic; Non-alcoholic Fatty Liver Disease |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Social Sciences (Sheffield) > Information School (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 08 Nov 2023 11:06 |
Last Modified: | 08 Nov 2023 11:06 |
Status: | Published |
Publisher: | Ovid Technologies (Wolters Kluwer Health) |
Refereed: | Yes |
Identification Number: | 10.1002/hep.30113 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:205055 |
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