Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis. Mus musculus

Genetic predisposition and environmental components contribute to an individuals’ non-alcoholic fatty liver disease (NAFLD) susceptibility. Therefore, we compared phenotypic variations of mouse strains extensively used in biomedical research during induction of high-fat diet (HFD)-mediated NAFLD and assessed transcriptional alterations in livers. In a time-resolved fashion we determined a wide spectrum of physiological parameters in C3HeB/FeJ (C3H), C57BL/6NTac, C57BL/6J, and 129P2/OlaHsd (129) males during a 7, 14, or 21 days HFD challenge and performed gene transcription analyses in steatotic livers. HFD exposure for 21 days progressively increased liver triacylglycerol concentrations (TAG) in 129. Strain-specific liver transcription profiles in this model suggest a transition from benign fatty liver to inflammation-associated NAFLD. No comparable changes were observed in C3H males where after an initial increase, hepatic TAG declined. In all genetic backgrounds hepatosteatosis was paralleled by a concerted repression of genes potentially increasing the liver’s vulnerability to oxidative stress damage thereby contributing to the progression of benign hepatosteatosis to NASH later on. The products of further identified strain-independent gene candidates might represent putative molecular links between the pathogenesis of NAFLD and cancer, insulin resistance, type 2 diabetes, and neurodegenerative disorders. Phenotypic characteristics and strain-dependent and -independent transcriptional changes in liver in different murine genetic backgrounds in this work can be exploited in the search for molecular mechanisms implicated in the development of HFD-mediated NAFLD, the investigation of potential therapeutic targets and in selecting a suitable murine genetic background for studies and mouse mutant engineering. Overall design: We performed gene expression microarray analysis on liver from C3HeB/FeJ (C3H), C57BL/6NTac, C57BL/6J, and 129P2/OlaHsd (129) males during 21 days HFD challenge.