Avicularin Attenuates Lead-Induced Impairment of Hepatic Glucose Metabolism by Inhibiting the ER Stress-Mediated Inflammatory Pathway

Abstract

Lead (Pb), an environmental hazard, causes several human diseases. Avicularin (Avi), a main dietary flavonoid found in several plants and fruits, exhibits potential protective properties on organs. However, the molecular mechanisms of Avi’s protective effects against Pb-induced damage are not clear. In our study, the effects of Avi on Pb-induced hepatotoxicity were evaluated using ICR mice. We have revealed for the first time that treatment with Avi significantly reduced hepatic inflammation, endoplasmic reticulum stress (ERS) and glucose metabolism disorder induced by Pb. Avi decreased the serum biochemical indicators of glucose metabolism. Avi increased the activities of glycogenolysis rate-limiting enzyme hexokinase (HK), pyruvate kinase (PK), glucokinase (GK) and glycogen phosphorylase (PYG) and inhibited the activities of gluconeogenesis rate-limiting enzyme phosphoenolpyruvate carboxy kinase (PEPCK) and glucose-6-phosphate dehydrogenase (G6PD). Avi decreased the protein expression levels of glucose-regulated protein 78 (GRP78), phosphorylated inositol requiring enzyme 1 (p-IRE1), phosphorylated RNA-dependent protein kinase-like ER kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α). The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were decreased in the liver as a result of Avi suppression Pb-induced inflammation. These results indicated that Avi attenuated Pb-induced impairment of hepatic glucose metabolism by the ERS and inflammation pathway.