Protective effects of acacetin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice

Agastache rugosa (Fisch. et Meyer) O. Kuntze (Labiatae), a perennial herb ubiquitous in Korean, has been widely used for treatment of fungal diseases, gastrointestinal disorders, and inflammatory diseases. This study examined the hepatoprotective effects of acacetin, a flavonoid isolated from A. rugosa, against D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were given an intraperitoneal injection of acacetin (25, 50 and 100 mg/kg) or the vehicle alone (5% DMSO-saline) 1h before GalN (800 mg/kg)/LPS (40 µg/kg) treatment, and sacrificed at 1 and 6h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity and these increases were attenuated by acacetin. GalN/LPS increased serum tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels. Acacetin attenuated TNF-α level, and further increased IL-6 level. GalN/LPS increased protein expression of toll-like receptor (TLR) 4, phosphorylation of extracellular signal-related kinase, p38 and c-Jun N-terminal kinase and nuclear protein expression of nuclear factor κB, and these increases were attenuated by acacetin. GalN/LPS activated autophagic flux as indicated by increased microtubule-associated protein 1 light chain 3-II and decreased sequestosome1/p62 protein expression. This activation was enhanced by acacetin. GalN/LPS increased Atg5 and Atg7 protein expressions, and these increases were augmented by acacetin. Our findings suggest that acacetin protects against GalN/LPS-induced liver injury by suppressing TLR4 signaling and enhancing autophagic flux.

Keywords: acacetin, Agastache rugosa, fulminant hepatic failure, inflammation, autophagy