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BACKGROUND AND AIM Obesity and type 2 diabetes increase hepatocellular carcinoma (HCC) incidence in humans, and accelerate diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. We investigated whether exercise reduces HCC development in obese/diabetic Alms1 mutant (foz/foz) mice, and studied protective mechanisms METHODS: We measured HCC development in DEN-injected male foz/foz and wildtype (Wt) littermates housed with or without exercise wheel from 4 until 12 or 24wks, and in foz/foz mice pair-fed to Wt littermates. We also studied HCC development in DEN-injected Jnk1-/-.foz/foz mice generated by cross breeding, as well as their genetic controls. Dysplastic hepatocytes were identified by GST-pi immunohistochemistry (IHC), liver nodules counted, and HCC analysed by histopathology RESULTS: Exercising foz/foz mice maintained similar weight as Wt to 10wks, but then gained weight and were obese by 24wks; a similar body weight profile was obtained by pair-feeding foz/foz mice to Wt. At 12wks, livers of exercising foz/foz mice exhibited fewer GST-pi positive hepatocytes than sedentary counterparts; by 24wks, fewer exercising foz/foz mice developed HCC (15% vs 64%, P<0.05). Conversely, pair-feeding foz/foz mice failed to reduce HCC incidence. In these insulin-resistant foz/foz mice, exercise failed to activate hepatic AMPK or Akt/mTORC1. Instead, it improved insulin sensitivity, ameliorated steatosis and liver injury, activated p53 to increase p27 expression, and prevented JNK activation. This was associated with suppression of hepatocellular proliferation. DEN-injected Jnk1-/-.foz/foz mice failed to develop liver tumors or HCC at 24wks CONCLUSIONS: Direct effects of exercise dampen proliferation of dysplastic hepatocytes to reduce 3-month dysplastic foci and 6-month incidence of DEN-induced HCC in obese, insulin-resistant mice. The effects of exercise of potential relevance to slowing of hepatocarcinogenesis include p53-mediated induction of p27 and prevention of JNK activation.