The Mechanisms Of Avicularin Improve Lead-induced Hepatic Gluconeogenesis Disorder In Mice Through AMPK-relate Signaling Pathways

Lead（Pb）is a common heavy metal,which is widely used in our lives.As the world’s second largest economy,China’s lead resources and production are among the highest in the world.Unfortunately,lead pollution is becoming more and more serious in the ecological environment,and lead accumulates in atmosphere,soils,lakes and oceans cannot be effectively purified and fixed.Many people passively intake excessive lead,which causes abnormally high blood glucose and liver damage.Hepatic gluconeogenesis is an important process to regulate blood glucose,but the disorder of gluconeogenesis can lead to high blood glucose.Avicularin（AL）is an active component of flavonoids,which widely found in Chinese medicinal materials such as Polygonum aviculare L.Avicularin has many important biological functions such as anti-inflammatory,anti-oxidant,anti-cancer and regulating blood glucose.We investigated the regulation mechanism of avicularin to hyperglycemia,liver damage and hepatic gluconeogenesis of AMPK-related signaling pathways in mice.Sixty SPF ICR（Institute of Cancer Research）mice were randomly divided into four groups:control group（200mg/LNa Ac）,Pb treatment group（200mg/L Pb（Ac）₂）,Pb+low avicularin treatment group（200mg/L Pb（Ac）₂+25mg/kg AL）,Pb+high avicularin group treatment（200mg/L Pb（Ac）₂+50mg/kg AL）,high avicularin treatment group（50mg/kg AL）.At the end of three months,mice were sacrificed by decapitation.Blood and liver were collected immediately for future experiments.The fasting blood glucose（FBG）,insulin levels and Pb content of each mouse were measured.Liver tissue sections were stained with HE staining.The indicators of liver injury,oxidative stress and the activities of hepatic gluconeogenesis-related enzymes were also determined.Besides,the expressions of hepatic gluconeogenesis-related m RNA and proteins,such as AMPK、NOX4、PI3K、AKT、TORC2、PGC1-α、NF-κB、PDE4B、PEPCK、G6Pase,were detected by q PCR and western blot staining.The results showed that lead could cause mentally sluggish.The amount of food intake decreased sharply due to Pb exposure.The hemorrhage and edema were the main symptoms of liver tissue.Furthermore,the edges of liver tissue were blunt and liver lobes were adhered.The liver cells were arranged chaotically and some cells were broken.Avicularin can improve liver injury in mice.Meanwhile,we found that avicularin can significantly reduce the fasting blood glucose,insulin and Pb levels in liver tissue of Pb-treated mice.The activities of ALT,AST and AKP in serum of Pb-treated mice were significantly increased.After avicularin treatment,the levels of liver injury were effectively inhibited.Then,the activations of the antioxidant enzymes GSH-Px,SOD,GST,in the livers of Pb-treated mice were significantly decreased.The lipid peroxidation MDA was significantly increased.Treatment with avicularin inhibited the oxidative stress in the livers of Pb-treated mice.The avicularin improved the expression levels of hepatic glycolysis and gluconeogenesis-related enzyme of mice.Finally,the m RNA and protein expression levels of p-AMPK,PI3K,p-AKT,and PDE4B were significantly increased and the expression levels of NOX4,TORC2,PGC1-α,NF-κB,G6Pase and PEPCK were significantly increased of Pb-treated mice.Avicularin inhibited these changes in mouse livers.The results proved that avicularin can improve blood glucose,liver damage and hepatic gluconeogenesis through AMPK and NOX4,TORC2,NF-κB signaling pathway.This study explored that avicularin attenuated hepatic gluconeogenesis metabolic disturbance by inhibiting liver injury,oxidative stress,inflammation and regulating AMPK signaling pathway in mice.It may provide data for improving metabolic disorder of gluconeogenesis induced by Pb.