Interstrain differences in susceptibility to non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) encompasses a clinico-pathologic spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter is widely considered as the first relevant pathophysiological step in NAFLD-progression, and epidemiological studies clearly indicate strong variation in the natural course of NAFLD in different ethnic groups.

The aim of this study was to assess whether there are also differences in the susceptibility to NASH between different mouse strains.

Methods and Results: Male C57BL/6, 129/SvJ and BALB/C mice (8 weeks old) were fed with high-fat diet (HFD), which has been shown to induce NASH that closely resembles pathopyhsiological changes observed in human NASH (Matsuzawa et al. Hepatology 2007). 12 weeks feeding of the HFD induced similar hepatic steatosis in all 3 mouse strains. However, the increase of serum transaminases and hepatic proinflammatory gene expression (TNF, IL-1, MCP-1) in response to HFD-feeding were significantly higher in 129/SvJ and BALB/C mice than in C57BL/6, while 129/SvJ and BALB/C mice did not differ significantly regarding these parameters. Also the liver-to-body eight ratio, profibrogenic gene expression (Collagen I, TIMP-1, TGF-beta) and histological fibrosis were significantly higher in HFD-129/SvJ than in HFD-C57BL/6 mice. However and interestingly, profibrogenic gene expression and fibrosis were even more increased in BALB/C than in 129/SvJ mice.

Conclusion: There is significant mouse strain-dependent variation in the susceptibility to NASH development and progression, and interestingly, these differences selectively affect hepatic inflammation an fibrosis. Identification of the precise molecular mechanisms of the interstrain differences may provide indications of the pathophysiological mechanisms of NASH (progression) in humans.