Cathepsin-B dependent autophagy ameliorates steatoheaptitis in chronic exercise rats
Rui Guo1*, Qian Yu1*, Emily C. Liong1, Man Lung Fung1,2 and George L. Tipoe1,2
1School of Biomedical Sciences and 2Brain Hormone Healthy Aging Centre,
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R.
* These authors have equal contributions.
Offprint requests to: George L. Tipoe, School of Biomedica Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, S.A.R. e-mail: tgeorge@hku.hk
Summary. Purpose. This study aimed to investigate the role of cathepsin B dependent autophagy induced by chronic aerobic exercise on a high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) in rats. Methods. Healthy female (Sprague-Dawley) SD rats (8-10 weeks old; 180g-200g; n=6 per group) were divided into: (1) control group; (2) HFD group; (3) Exercise group; (4) HFD + exercise group. Rats were fed with a normal chow or an HFD for 12 weeks. Rats with exercise ran on a rotarod for 30 min per day from weeks 9-12. Results. Exercise training significantly (1) upregulated the levels of autophagy markers Beclin1, ATG5 and LC3II partly through inhibiting the p-AKT/mTOR pathway; (2) ameliorated HFD-mediated accumulation of fat mass by upregulating β-oxidation regulator PPAR-α and downregulating fatty acid synthesis marker SREBP-1c via lipophagy; (3) diminished the HFD-induced hepatic pro-inflammatory mediators TNF-α and IL-1β via NF-κB inactivation; (4) decreased the NASH-induced hepatic apoptotic marker caspase-3 activation caused by the upstream oxidative stress and by cytochrome P450 2E1 (CYP2E1); (5) mitigated the HFD-mediated lysosomal membrane permeabilisation and cathepsin B release partly via the reduction of reactive oxygen species (ROS). Conclusions. Chronic aerobic exercise reduces oxidative stress/ROS and ROS may cause lysosomal membrane destabilisation and disrupts the autophagic process. The beneficial effect of chronic exercise may further inhibit the process of lysosome membrane permeabilisation and facilitate lysosome fusion with autophagosomes to trigger autophagy. This process may possibly contribute to the inhibition of cathepsin B released into cytosol which further reduces inflammation and mitochondrial-dependent apoptosis. Histol Histopathol 35, 833-847 (2020)
Key words: Aerobic exercise, Autophagosome, lysosomal membrane, Oxidative stress, Apoptosis
DOI: 10.14670/HH-18-204