Gender-specific differences in a murine model of non-alcoholic steatohepatitis

Only a fraction of patients with nonalcoholic fatty liver progress to steatohepatitis (NASH). Epidemiological studies revealed gender-specific differences in both prevalence and severity of NASH, however, data are still contradictory.

The aim of this study was to assess whether there are gender-specific differences in a dietary model of non-alcoholic steatohepatitis in mice.

Methods and Results: Male and female C57BL/6 mice (7 weeks old) were fed with a 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) for 38 weeks. Interestingly, body weight-gain was significantly higher in male than in female mice, while hepatic content of triglycerides, cholesterol and free fatty acids were only moderately higher in HFD-fed male compared to HFD-fed female mice. However, increase of serum transaminases, hepatic pro-inflammatory (TNF, IL-1, MCP-1, RANTES, ICAM-1) and pro-fibrogenic (Collagen I, TIMP-1, TGF-beta) gene expression, activation of hepatic stellate cells, hepatic hydroxyproline content and histological fibrosis were significantly higher in HFD-male than in HFD-female mice. Furthermore, leukocytes were analyzed by flow cytometry in peripheral blood. Here, both male and female HFD-mice showed an significant but similar accumulation of myeloid cells. In contrast, T cells were reduced to HFD-feeding but primarily in male mice. No effect was found for NK cells and B cells.

Conclusion: We observed significant gender-specific variation in the susceptibility to NASH development and progression in a murine dietary model, which may be caused by concomitant metabolic and immunological alterations. Identification of the molecular mechanisms of these gender-specific differences may provide insight into the pathogenesis of NAFLD and may built the basis for new prognostic markers and therapeutic targets also.