Exercise improves outcomes of surgery on fatty liver and can be substituted through AMPK activation - an experimental study

Abstract

Background: Steatosis is a serious risk factor for liver surgery and transplantation, mostly because of its impact on ischemic tolerance (IT) and regenerative capacity (RC) of the liver. Exercise is most effective in counteracting steatosis, but how it affects IT and RC is unclear. Compound mimetics of physical activity are of major interest for patients who are unable to comply with exercise. Methods: A standardized mouse model of diet-induced steatosis was used. Obese mice were subjected for four weeks to regular exercise or treatment with AICAR, an activator of the key energy sensor induced through exercise, AMPK (adenosine monophosphate kinase). Mice were then exposed to hepatic ischemia or hepatectomy. Results: Exercise activated AMPK, normalized metabolic parameters, and improved IT and RC of fatty liver. Similar, albeit smaller, improvements were noted for lean liver, indicating steatosis-independent effects of exercising. AICAR treatment had an impact on fatty liver akin to exercise. The power of AMPK activation in improving surgical outcomes was demonstrated in an established model of the small-for-size-syndrome, with exercising raising survival from 20 to 80%. Conclusion: Any safe intervention reducing hepatic fat accumulation and improving IT and RC is most welcome in liver surgery. Exercising is powerful but its application is limited. Our findings suggest that pharmacological AMPK activation is a promising strategy to sustain the surgical benefits of exercise in the absence of compliance issues.