The Genetic Architecture of Diet‐Induced Hepatic Fibrosis in Mice

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.

Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high‐fat diet in the genetically diverse Collaborative Cross mouse model

“…This indicates that analysis of the expression of fibrosis marker genes can be used for monitoring the progression of NAFL to NASH. Similar results of early upregulation fibrosis marker genes, including Col1a1 and Tnf , and a high Krt8/Krt18 ratio were observed in a diet‐induced mouse model of hepatic fibrosis 18 and in a Krt18 −/− transgenic mouse model of NASH 31 …”

“…Unfortunately, the study does not interrogate the impact of genetic differences within a genetically diverse population for the development of NAFLD due to insufficient genetic diversity in this model. To address this limitation, several studies have used a population‐based approach to investigate the molecular pathogenesis of NAFLD induced by obesogenic high‐fat and high‐sucrose (HF/HS) diets in the Hybrid Mouse Diversity Panel (HMDP) 16,17 or BXD recombinant strains 18 . These studies have identified fundamental molecular phenotypes and metabolic and transcriptomic pathways associated with the development and progression of NAFLD; however, the role of sex‐specific alterations that contribute to the pathogenesis of human NAFLD 19 remained unanswered because only male mice were used 16‐18 …”

Of Mice and Men and Nonalcoholic Steatohepatitis

“…The current study elegantly demonstrated the importance of mouse strains by feeding a Western diet to over 100 mouse strains. Mice that developed steatosis or NASH with fibrosis varied greatly across strains, such as HMDP mice developing HS without fibrosis and BXD19/Ty mice developing hepatic fibrosis …”

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…Although current preclinical NAFLD models can be considered indispensable tools for studying chronic liver disease pathology, it should be noted that the majority of existing rodent models mainly focus on certain stages of the disease rather than the total spectrum. Additionally, it is noteworthy that the NAFLD disease progression greatly varies across different strains [140]. Therefore, depending on its research question, careful model selection is highly recommended.…”