Aescin can alleviate NAFLD through Keap1-Nrf2 by activating antioxidant and autophagy

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic liver disease worldwide. It has been proven that aescin (Aes), a bioactive compound derived from the ripe dried fruit of Aesculus chinensis Bunge, has a number of physiologically active properties like anti-inflammatory and anti-edema, however it has not been investigated as a potential solution for NAFLD. This study's major goal was to determine whether Aes can treat NAFLD and the mechanism underlying its therapeutic benefits. We constructed HepG2 cell models in vitro that were affected by oleic and palmitic acids, as well as in vivo models for acute lipid metabolism disorder caused by tyloxapol and chronic NAFLD caused by high-fat diet. We discovered that Aes could promote autophagy, activate the Nrf2 pathway, and ameliorate lipid accumulation and oxidative stress both in vitro and in vivo. Nevertheless, in Autophagy-related proteins 5 (Atg5) and Nrf2 knockout mice, Aes lost its curative impact on NAFLD. Computer simulations show that Aes might interact with Keap1, which might allow Aes to increase Nrf2 transfer into the nucleus and perform its function. Importantly, Aes's stimulation of autophagy in the liver was hampered in Nrf2 knockout mice. This suggested that the impact of Aes in inducing autophagy may be connected to the Nrf2 pathway. We first discovered Aes's regulating effects on liver autophagy and oxidative stress in NAFLD. And we found Aes may combine the Keap1 and regulate autophagy in the liver by affecting Nrf2 activation to exert its protective effect.