Kaempferol Protects Mice from D-GalN/LPS-induced Acute Liver Failure by Regulating the Autophagy Pathway

Abstract Background Kaempferol, a flavonoid compound present in many edible plants, has been used in traditional medicine and has various biological functions. Acute liver failure (ALF) is a lethal clinical syndrome with severe liver function damage. There are currently no effective treatments for ALF except for liver transplantation. The aim of this study is to explored the mechanisms underlying the therapeutic effect of kaempferol in ALF. Methods The ALF mouse model was established using D-galactosamine (D-GalN, 700 mg/kg)/lipopolysaccharide (LPS, 10 µg/kg). Two hours before the administration of D-GalN/LPS, different group of mice were pretreated according different doses of kaempferol, 6 hours after injection of D-GalN/LPS, and then killed. The survival rate, liver function and inflammatory cytokine levels were assessed. It was determined whether kaempferol pretreatment protected hepatocytes from ALF induced by D-GalN/LPS via autophagy pathway in vivo and in vitro. Results Pretreatment with a high dose of kaempferol significantly decreased the survival rate and increased severe liver damage; however, pretreatment with a low dose of kaempferol showed the opposite effect. Furthermore, pretreatment with a high dose of kaempferol augment the levels of proinflammatory cytokines and markers of the MAPK signaling pathway, while pretreatment with a low dose of kaempferol showed the opposite effect. In addition, pretreatment with a high dose of kaempferol decreased autophagy, but pretreatment with a low dose of kaempferol increased autophagy in vivo and in vitro. It was also proved that pretreatment with 3-methyadenine (3- MA) or Atg7 siRNA to inhibit autophagy partially negated the hepatoprotective effect of kaempferol (5 mg/kg) pretreatment in ALF mice induced by D-GalN/LPS. Conclusions Our findings demonstrate that effects of different doses of kaempferol on D-GalN/LPS-induced ALF is remarkably different by regulating the autophagy pathway. Therefore, we should consider selecting the optimal dose of kaempferol as a potential treatment method for patients with ALF.