RESUMO
PURPOSE: To investigate the novel molecular mechanisms of the antioxidant and anti-inflammatory properties of S-allylmercaptocysteine (SAMC) based on a transcriptomic study in a nonalcoholic steatohepatitis (NASH) rat model METHODS: NASH was induced in Sprague-Dawley rats by feeding with a high fat diet (HFD) for 12 weeks. 200 mg/kg SAMC was fed by oral gavage for 4 weeks from 9 to 12 week. RESULTS: SAMC co-administration attenuated HFD-induced liver injury, including the increased serum ALT, hepatic oxidative stress and inflammation. Transcriptomic analysis revealed that SAMC dramatically induced the XRE- and ARE-driven drug metabolising enzymes (DMEs) including Akr7a3, Akr1b8, and Nqo1. The nuclear translocation of the upstream regulator of xenobiotics metabolism, AHR, and regulator of antioxidant responses, NRF2, were significantly increased by SAMC treatment. Furthermore, SAMC counteracted the effects of HFD on NF-κB/IκB and NLRP3/6 pathways with decreasing protein levels of ASC, cleaved caspase-1, IL-18, and IL-1ß. These results were further verified in another mice NASH model induced by an MCD diet with SAMC co-administration. CONCLUSION: We propose that SAMC triggers AHR/NRF2-mediated antioxidant responses which may further suppress the NLRP3/6 inflammasome pathway and NF-κB activation, contributing to the improvement of NASH.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Preparações Farmacêuticas , Animais , Cisteína/análogos & derivados , Inflamação/tratamento farmacológico , Fígado , Camundongos , Fator 2 Relacionado a NF-E2/genética , Inibidor de NF-kappaB alfa , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ratos , Ratos Sprague-DawleyRESUMO
The present study aimed to investigate the molecular mechanisms of the ameliorative effects of chronic aerobic exercise on nonalcoholic steatohepatitis (NASH) in rat skeletal muscle. Female SpragueDawley rats (n=69 per group) were divided into four groups: i) Rats fed with normal chow; ii) exercise rats fed with normal chow + exercise (run on a rotarod for 30 min per day from 912 weeks); iii) rats fed with a highfat diet (HFD); iv) rats fed with an HFD + exercise. All HFD rats were fed with an HFD consisting of 30% fat from fish oil throughout the study for 12 weeks. Exercise decreased the levels of hepatic lipogenic markers carbohydrateresponsive elementbinding protein, fatspecific protein 27 and liver X receptor and improved systemic glucose and insulin intolerance in the NASH animal model. The beneficial effects may have been mediated partly via the tripartite motifcontaining family protein 72 (TRIM72)/PI3K/Akt/mTOR pathway, accompanied with an upregulation of glucose transporter 4 in the skeletal muscle. The exercise regimen activated the master regulator of antioxidant enzymes, nuclear factor erythroid 2related factor 2, with upregulation of superoxide dismutase [CuZn] expression and a corresponding decrease in kelchlike ECHassociated protein 1 expression, but failed to decrease the levels of the oxidative marker malondialdehyde in the HFD rat skeletal muscle. Chronic exercise decreased the expression of the inflammation marker NFκB, followed by a decrease in interleukin6 and tumor necrosis factorα levels, as verified by a corresponding increase in the level of NFκB inhibitor α expression. Exercise may exert its beneficial effects by improving muscle insulin sensitivity via the TRIM72/PI3K/Akt/mTOR pathway, contributing to the improvement of systemic insulin intolerance, and finally leading to decreased hepatic lipogenesis during NASH. The attenuation of insulin resistance by exercise may be partly achieved through a decrease in the level of inflammation and an increased antioxidant response.