Aging promotes hepatocellular steatosis, inflammation and fibrosis in non-alcoholic steatohepatitis in mice

Nonalcoholic steatohepatitis involves necroinflammatory activity and fibrosis, which are believed to be mediated by lipotoxicity caused by toxic metabolites from excess fatty acids. 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 lipotoxicity and NASH in primary hepatocytes and a dietary murine model, respectively.

Methods and Results: Upon stimulation with free fatty acids hepatocytes isolated from 4 week old mice revealed a significantly higher intracellular lipid accumulation and pro-inflammatory gene expression than hepatocytes isolated from 14 week old mice. Furthermore, we started feeding a high fat diet (HFD) to male C57BL/6 mice at the age of 4 or 14 weeks. 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 both age classes as compared to control mice fed with standard chow. Furthermore, hydroxynonenal staining and increased Ncf–1 and Nox2 expression were indicative for oxidative stress. However, all these changes were significantly higher in the old mice. Similarly, serum transaminase levels, hepatic pro-inflammatory (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 the older mice.

Conclusion: There is significant age-dependent variation in the susceptibility to NASH development and progression, which seems to be caused at least in part by differences in the lipid metabolisms in the hepatocytes. The identification of the underlying (molecular) mechanisms of these differences may have prognostic as well as therapeutic implications for the progression of NAFLD.

NAFLD - NASH - age - lipotoxicity