Guarino, Maria (2020) Regular exercise prevents the transition from fatty liver to steatohepatitis. [Tesi di dottorato]

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Background: Lifestyle interventions incorporating exercise remain the cornerstone of treatment for non-alcoholic fatty liver disease (NAFLD), which can progress to steatohepatitis (NASH), fibrosis and hepatocellular carcinoma (HCC). Yet it remains uncertain whether exercise alone is beneficial to the outcome of fibrotic NASH when dietary changes have been unsuccessful. Therefore, we queried whether exercise arrests the histological and carcinogenic progression of NASH in an experimental, choline-deficient high-fat diet (CD-HFD) murine model. Methods: Male C57Bl/6N mice were assigned randomly to either control diet (n=11) or CD-HFD (n=33). At 12 weeks, control tissues were harvested and the CD-HFD mice were randomized either for tissue harvest (n=11) or for 8 further weeks of sedentariness (SED, n=11) or treadmill exercise (EXE, n=11) (1h, 5days/week, speed 12.5m/min). Changes in plasma biochemistry, liver histology, tumor burden, electron microscopy, protein expression and mitochondrial bioenergetics (Oxygraph-2k Oroboros) were assessed. Results: After 12 weeks of CD-HFD, mice developed NAFL. After 20 weeks of CD-HFD, SED mice developed NASH and hepatic adenomas. However, exercise halted the progression of NAFL to NASH. EXE livers showed lower triglycerides, lower TNFα expression, less fibrosis, less ballooning and a lower NAFLD activity score (median 6 vs 8; p<0.001) than did SED livers. Plasma ALT, triglycerides, cholesterol and total bile acids were also lower in EXE than in SED (p<0.05). Exercise activated liver authophagy as indicated by the increase in LC3-II/LC-I and recruitment of phosphorylated PINK to the mitochondria. Moreover, exercise activated AMPK with consequent inhibition of mTORC1 and decreased phosphorylation of S6, reducing the incidence of hepatocellular adenoma (70% vs 100% for EXE vs SED, respectively, p<0.001). However, the CD-HFD triggered ER stress and the pro-apoptotic pathway as shown by the increase in CHOP and ratio of Bax/Bcl2 and exercise did not prevent this. In keeping with the pro-apoptotic state, CD-HFD treated mitochondria displayed higher leak respiration, and a lowered maximal and complex IV driven respiration. Exercise did not change the mitochondrial bioenergetics. The CD-HFD provoked sinusoidal endothelial defenestration, which was not restored by exercise. Conclusions: In an experimental model of established NAFLD, exercise arrests the transition from NAFL to NASH. Moreover, exercise improves biochemical and histological parameters of NAFLD and impedes the progression of fibrosis and liver carcinogenesis through activating the AMPK signaling pathway and favoring liver autophagy. Our work supports the benefits of exercise independently of other lifestyle changes.

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