The hepatoprotective effect of myricetin against lipopolysaccharide and D-galactosamine-induced fulminant hepatitis

Abstract

Fulminant hepatitis (FH) is a severe liver disease characterized by extensive hepatic necrosis, oxidative stress, and inflammation. Myricetin (Myr), a botanical flavonoid glycoside, is recognized to exert antiapoptosis, anti-inflammatory, and antioxidant properties. In the current study, we focused on exploring the protective effects and underlying mechanisms of Myr against lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced FH. These data indicated that Myr effectively protected from LPS/D-GalN-induced FH by lowering the mortality of mice, decreasing ALT and AST levels, and alleviating histopathological changes, oxidative stress, inflammation, and hepatic apoptosis. Moreover, Myr could efficiently mediate multiple signaling pathways, displaying not only the regulation of caspase-3/9 and P53 protein, inhibition of toll-like receptor 4 (TLR4)-nuclear factor-kappa B (NF-κB) activation, and -mitogen-activated protein kinase (MAPK), but also the increase of heme oxygenase-1 (HO-1) and nuclear factor-erythroid 2-related factor 2 (Nrf2) expression, as well as induction of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in mice with LPS/D-GalN-induced FH. Importantly, our further results in vitro suggested that Myr remarkably attenuated H₂O₂-triggered hepatotoxicity and ROS generation, activated Keap1-Nrf2/HO-1 and AMPK/ACC signaling pathway. However, Myr-enhanced the expression of HO-1 and Nrf2 protein was reversed by Keap1-overexpression, Nrf2-null and AMPK inhibitor. Meanwhile, Myr-relieved hepatotoxicity excited by H₂O₂ was blocked by Nrf2-null and AMPK inhibitor. Taken together, Myr exhibits a protective role against LPS/D-GalN-induced FH by suppressing hepatic apoptosis, inflammation, and oxidative stress, likely involving in the regulation of apoptosis-related protein, TLR4-NF-κB/-MAPK and NLRP3 inflammasome, and AMPK-Nrf2/HO-1 signaling pathway.

Keywords: Fulminant hepatitis; Hepatic necrosis; Inflammation; Myricetin; Oxidative stress; Signaling pathway.