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.

No abstract

Lead (Pb), an environmental hazard, causes severe diseases in the liver, kidney, cardiovascular system, hematopoietic system, reproductive system, and nervous system. Avicularin (AVI), the main dietary flavonoid found in many citrus fruits, exhibited potential protective properties on organs. However, the molecular mechanisms of these protective actions are currently not clear. In our study, the effects of AVI on Pb-induced hepatotoxicity were evaluated using ICR mice. Changes in oxidative stress, inflammation, lipid metabolism, and related signaling were evaluated. We found for the first time that treatment with AVI significantly reduced hepatic steatosis, inflammation, and oxidative stress induced by Pb. AVI attenuated Pb-induced liver dysfunction and lipid metabolism disorder in mice. AVI decreased the serum biochemical indicators of lipid metabolism. AVI decreased the expression levels of lipid metabolism-related protein SREBP-1c, acetyl-CoA carboxylase (ACC), and FAS. AVI suppressed Pb-induced inflammation in livers, as indicated by decreasing the TNF-α and IL-1β levels. AVI suppressed oxidative stress by increasing the activation of SOD, CAT, and GPx. Furthermore, AVI inhibited the activities of JNK, ERK, p38, and NF-κB. AVI further decreased the levels of HSP60, NLRP3, p-IκBα, and p-p65 in the livers of mice. Collectively, this study indicated that AVI mitigated Pb-induced hepatic steatosis, oxidative stress, and inflammation by regulating the SREBP-1c and MAPK/HSP60/NLRP3 signaling pathways.