The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice

Simon T. Hui*, Zeyneb Kurt, Iina Tuominen, Frode Norheim, Richard C.Davis, Calvin Pan, Darwin L. Dirks, Clara E. Magyar, Samuel W. French, Karthickeyan Chella Krishnan, Simon Sabir, Francisco Campos-Pérez, Nahum Méndez-Sánchez, Luis Macías-Kauffer, Paola León-Mimila, Samuel Canizales-Quinteros, Xia Yang, Simon W. Beaven, Adriana Huertas-Vazquez, Aldons J. Lusis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)2182-2196
Number of pages15
JournalHepatology
Volume68
Issue number6
DOIs
Publication statusPublished - 8 Nov 2018
Externally publishedYes

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