Protective mechanisms of chronic aerobic exercise and S-allylmercaptocysteine on non-alcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of liver disease worldwide, which is closely associated with other metabolic syndrome such as obesity and type II diabetes and appears to be related to an increasing sedentary and poor dietary lifestyle. Currently, exercise is a first line therapeutic intervention for NAFLD/non-alcoholic steatohepatitis (NASH) management and at the same time hepato-protective traditional herbal derivatives are gaining much attention as supplementary treatment strategy for NAFLD. In this study, we investigated the beneficial effects and molecular mechanisms of aerobic exercise (lifestyle modification) and garlic derived S-allylmercaptocysteine (SAMC) (herbal derivative) in the pathogenesis of NAFLD/NASH. There are two major hypotheses in this study namely: a) chronic exercise training decreases inflammation and increases antioxidant responses in muscle, which might contribute to the enhancement of muscle insulin sensitivity partly through TRIM72/PI3K/Akt/mTOR pathway and the improvement of systemic insulin intolerance, and ultimately leading to amelioration of NASH; b) SAMC ameliorates NASH partly through induction of hepatic cytoprotective enzymes which may be dependent on AhR/Nrf2 pathway, leading to the suppression of NF-κB/IκBα pathway and NLRP3/6 inflammasomes activation, and ultimately contributing to the improvement of NASH. In this study, NASH was induced in two models including a) Sprague-Dawley rats fed with a high fat diet (HFD) containing 30% from fish oil for 12 weeks, and b) mice NASH model fed with a methionine-choline deficient (MCD) diet. In the first study, the protective mechanisms of aerobic exercise on NAFLD were investigated in the NASH rat model. Four-week exercise training 1) decreased body weight and fat mass; 2) attenuated hepatic histological injury; 2) reduced serum ALT level; 3) reduced serum free fatty acids (FFA), hepatic triglycerides (TG) contents and hepatic lipogenesis; 4) restored systemic glucose and insulin intolerance; 5) improved muscle insulin sensitivity partly through TRIM72/PI3K/Akt pathway, accompanied with an upregulation of glucose transporter 4 (GLUT4); 6) increased antioxidant responses partly under the regulation of Nrf2/Keap1 pathway in the muscle; and 7) decreased expressions of pro-inflammatory cytokines through NF-κB/IκBα pathway in the skeletal muscle. In the second study, the protective mechanisms of SAMC were investigated in the livers of both rat and mice NASH models, which showed 1) reduced body weight and fat mass; 2) attenuated hepatic histological injury; 3) improved NAFLD-related features including decreased serum ALT levels, reduced serum FFA and hepatic TG contents; 4) ameliorated hepatic oxidative stress; 5) induced xenobiotic response element (XRE)- and antioxidant response element (ARE)-driven drug metabolising enzymes (DMEs) including Akr7a3, Akr1b8, and NQO1 based on global transcriptomic profiles by RNA-sequencing in whole-liver tissues; 6) increased the nuclear translocation of AhR and Nrf2 which were master regulators of xenobiotic and antioxidant responses, respectively; 7) decreased protein expression of nuclear transcription factor NF-κB and hepatic production of proinflammatory cytokines; 8) diminished NLRP3 and NLRP6 inflammasomes. In conclusion, the present study proposes that both exercise training and garlic are effective in modulating the progression and outcome of NAFLD/NASH which could be used as supplementary therapeutic management strategy for NAFLD/NASH.