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The Genetic Architecture of Diet‐Induced Hepatic Fibrosis in Mice
Author(s) -
Hui Simon T.,
Kurt Zeyneb,
Tuominen Iina,
Norheim Frode,
C.Davis Richard,
Pan Calvin,
Dirks Darwin L.,
Magyar Clara E.,
French Samuel W.,
Chella Krishnan Karthickeyan,
Sabir Simon,
CamposPérez Francisco,
MéndezSánchez Nahum,
MacíasKauffer Luis,
LeónMimila Paola,
CanizalesQuinteros Samuel,
Yang Xia,
Beaven Simon W.,
HuertasVazquez Adriana,
Lusis Aldons J.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30113
Subject(s) - steatosis , fibrosis , biology , nonalcoholic fatty liver disease , steatohepatitis , hepatic fibrosis , apolipoprotein b , genetic model , pathology , medicine , fatty liver , endocrinology , disease , genetics , gene , cholesterol
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.