Heterozygous p53 knockout affects development of obesity, insulin resistance and non-alcoholic steatohepatitis in mice fed with a Western type diet

The tumor suppressor p53 is a primary sensor of stressful stimuli. It controls several biologic processes and plays a central role in hepatocarcinogenesis. p53 deficient (p53 -/-) mice spontaneously develop intra- and extra-hepatic malignancies, and recently, it has been shown that they develop less hepatocellular damage and fibrosis upon feeding the NASH-inducing methionine- and choline-deficient (MCD) diet.

The aim of this study was to analyze the function of p53 in a model which more accurately simulates human NASH in the context of the metabolic syndrome.

Methods and Results: p53 heterozygote knockout mice (p53-/+) and wildtype C57Bl/6 control mice were fed with a NASH inducing Western type diet (high fat, cholesterol and fructose). We used (p53-/+) rather than (p53 -/-) mice to avoid tumor formation. The weight gain caused by the NASH-diet was significantly higher in p53-/+ compared control mice with the first 6 weeks of feeding and glucose tolerance was impaired in p53-/+ but not in control mice. Thereafter, weight remained stable in p53-/+ mice but continued to rise in wt-mice and reached the level of p53-/+ after 11 weeks of feeding. At this time the experiments was terminated. NASH-diet induced hepatic triglyceride levels, serum transaminases levels, and expression levels of markers of oxidative stress (heme oxygenase 1), inflammation (MCP-1) and fibrosis did not differ significantly between p53-/+ and wt-controls.

Summary and Conclusion: Reduced p53 expression as observed in p53-/+ mice affects body weight gain and glucose tolerance in response to a Western type diet. Although these known NASH promoting factors assimilated during the course of feeding one could have expected more severe hepatocellular damage in p53-/+ mice. However and also different than observed in the MCD-model hepatic steatosis, inflammation and fibrosis were similar in p53-/+ and wt-mice. These finding could indicate the p53 effects vary during NAFLD-progression via both extra- and intra-hepatic mechanisms.