Endurance exercise-mediated metabolic reshuffle attenuates high-caloric diet-induced non-alcoholic fatty liver disease

Introduction and aim: Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in the United States. Metabolic distress (obese diabetes) is the main causative element of NAFLD. While there is no cure for NAFLD, endurance exercise (EEx) has emerged as a therapeutic strategy against NAFLD. However, mechanisms of EXE-induced hepatic protection especially in female subjects remain unidentified. Thus, the aim of the study is to examine molecular mechanisms of EXE-induced hepatic protection against diet-induced NAFLD in female mice. Material and methods: Nine-week-old female C57BL/6J mice were randomly divided into three groups: normal-diet control group (CON, n=11); high-fat diet/high-fructose group (HFD/HF, n=11); and HFD/HF+EEx group (HFD/HF+EEx, n=11). The mice assigned to HFD/HF and HFD/HF+EEx groups were fed with HFD/HF for 12 weeks, after which the mice assigned to the EEx group began treadmill exercise for 12 weeks, with HFD/HF continued. Results: EEx attenuated hepatic steatosis, reduced de novo lipogenesis (reduction in ATP -Citrate-Lyase and diacylglycerol-O-acyltransferase 1), and enhanced mitochondrial biogenesis and fatty-acid activation (oxidative phosphorylation enzymes and Acyl-CoA synthetase1). Also, EEx prevented upregulation of gluconeogenic proteins (glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphatase, and phosphoenolpyruvate-carboxykinase1), premature senescence (suppression of p53, p22, and p16, tumor-necrosis-factor-alpha, and interleukin-1 beta, and oxidative stress), and autophagy deficiency. Furthermore, EXE reversed apoptosis arrest (cleaved cysteine-dependent-aspartate-directed protease3 and Poly-(ADP-ribose)-polymerase1). Conclusion: EEx-mediated reparations of metabolic and redox imbalance (utilization of pentose phosphate pathway), and autophagy deficiency caused by metabolic distress critically contribute to preventing/delaying severe progression of NAFLD. Also, EEx-induced anti-senescence and cell turnover are crucial protective mechanisms against NAFLD. (C) 2022 Fundacion Clinica Medica Sur, A.C. Published by Elsevier Espana, S.L.U.

Automated summary

The aim of this study was to examine the molecular mechanisms of endurance exercise-induced hepatic protection against diet-induced non-alcoholic fatty liver disease (NAFLD) in female mice. The results showed that endurance exercise attenuated hepatic steatosis, reduced de novo lipogenesis, enhanced mitochondrial biogenesis, activated fatty-acid metabolism, prevented gluconeogenesis, senescence, oxidative stress, and autophagy deficiency, and reversed apoptosis arrest. These findings suggest that endurance exercise plays a crucial role in preventing/delaying the progression of NAFLD and protecting against its complications.