Aging promotes susceptibility to non-alcoholic steatohepatitis in mice

Nonalcoholic fatty liver disease (NAFLD) is considered as hepatic manifestation of the metabolic syndrome. In a subset of cases hepatic steatosis progresses to steatohepatitis (NASH), which may further advance with significant fibrosis. Epidemiological studies indicate that age has impact on the natural course of NAFLD.

The aim of this study was to assess whether there are age dependent differences in the susceptibility to NASH in a dietary murine model.

Methods and Results: A high fat diet (HFD) was fed to male C57BL/6 mice at three different age groups: 4, 14 and 24 weeks old. After 12 weeks HFD-feeding we observed a significant increase of body weight and liver-to-body weight ratio as well hepatic triglyceride and free-fatty-acid levels and histological steatosis in mice of all age classes as compared to control mice fed with standard chow. However, relative body weight gain and hepatic steatosis were significantly higher in 14 and 24 weeks old mice than in 4 week old mice. Serum transaminasen were not affected by HFD in 4 week old mice but exhibited a marked increase in both older groups. Similarly, hepatic proinflammatory (TNF, IL-1, MCP-1) and pro-fibrogenic (TGF-beta, TIMP-1, Collagen I) gene expression, activation of hepatic stellate cells (evidenced by alpha-sma expression), histological matrix deposition and fibrosis were significantly higher in older mice than younger mice fed with HFD.

Conclusion: There is significant age-dependent variation in the susceptibility to NASH development and progression, which affects hepatic lipid accumulation, inflammation and fibrosis. The identification of the underlying (molecular) mechanisms of these differences may have prognostic as well as therapeutic implications for the progression of NAFLD.