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Exercise retards hepatocarcinogenesis in obese mice independently of weight control

Published:April 16, 2020DOI:https://doi.org/10.1016/j.jhep.2020.02.006

      Highlights

      • Obesity and insulin resistance accelerate liver cancer onset in foz/foz mice.
      • Mice with an in-cage exercise wheel engage in physical activity that abolishes the effect of obesity on hepatocarcinogenesis.
      • Pair-fed foz/foz mice exhibit similar weight gain but are not protected.
      • Exercise decreases proliferation of dysplastic hepatocytes by activating p53 to induce p27.
      • A critical pathogenic role of JNK1 was also confirmed using Jnk1-/-.foz/foz mice.

      Background & Aims

      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 wild-type (WT) littermates housed with or without an exercise wheel from week 4 until 12 or 24 weeks, 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 glutathione-S-transferase pi form (GST-pi) immunohistochemistry, liver nodules were counted, and HCC was analysed by histopathology.

      Results

      Exercising foz/foz mice maintained similar weight as WT mice up to 10 weeks, but then gained weight and were obese by 24 weeks; a similar body weight profile was obtained by pair-feeding foz/foz mice to WT. At 12 weeks, livers of exercising foz/foz mice exhibited fewer GST-pi positive hepatocytes than sedentary counterparts; by 24 weeks, 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 tumours or HCC at 24 weeks.

      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 that potentially slow hepatocarcinogenesis include p53-mediated induction of p27 and prevention of JNK activation.

      Lay summary

      Fatty liver disease commonly occurs alongside obesity and diabetes, contributing to rapidly increasing rates of liver cancer throughout the world. Herein, we show that exercise reduces the incidence and progression of hepatocellular carcinoma in mouse models. The effect of exercise on cancer risk was shown to be independent of changes in weight. Exercise could be a protective mechanism against liver cancer in at-risk individuals.

      Graphical abstract

      Keywords

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      Linked Article

      • Reply to: “Switching vs. add-on strategy in PBC treatment: Lessons from UDCA and bezafibrate experience”
        Journal of HepatologyVol. 72Issue 6
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          We thank Dr. Corpechot et al. for their important thoughts on the treatment strategy in primary biliary cholangitis (PBC) now several second-line treatment options have become available. Their data on the use of add-on bezafibrate in patients with an incomplete biochemical response to ursodeoxycholic acid (UDCA) have convincingly shown that this agent can markedly improve biochemical liver tests and may thereby improve long-term clinical outcomes as predicted by parallel changes in prognostic scores, such as the GLOBE and UK-PBC score.
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