<i>L</i> -Theanine/ <i>α</i> -ketoglutarate/Nrf2 axis promotes exercise-mediated amelioration of nonalcoholic steatohepatitis in mice

<i>L</i>-Theanine (LTA) is a non-protein amino acid mainly found in tea plants with many beneficial effects. Exercise exerts a wide range of benefits in metabolic health. Here, we show that exercise or gastric lavage intervention on mice with LTA improves diet-induced nonalcoholic steatohepatitis (NASH) in mice. Meanwhile, combinatory therapy shows that exercise and LTA synergistically improve obesity-related metabolic disorders and NASH phenotypes, including hepatic steatosis, inflammation, cell death and oxidative stress. <i>In vivo</i> studies indicate that LTA inhibits free fatty acid (FFA)-induced hepatocyte injury, including steatosis, oxidative stress and apoptosis. Knockdown of <i>Nrf2</i> blunts the role of LTA in inhibiting FFA-induced hepatocyte oxidative stress and dysfunction. Mechanistically, LTA increases the <i>α</i>-ketoglutarate (<i>α</i>-KG) level in hepatocytes, which increases the transcription of <i>Nrf2</i> by inducing active DNA demethylation on its promoter. Moreover, LTA promote the above <i>α</i>-KG/Nrf2 axis in synergy with exercise, thereby more efficiently inhibiting hepatic oxidative stress and ameliorating diet-induced NASH in mice. Our results suggest that, through promoting the <i>α</i>-KG/Nrf2 axis-mediated anti-oxidative pathway, the combination of LTA and exercise may provide an effective measure for the prevention and control of NASH.