Molecular mechanism underlying the effects of licochalcone A on abnormal gluconeogenesis and endoplasmic reticulum stress induced by type 2 diabetes mellitus
The aim of this study is to investigate the molecular mechanism of licochalcone A(LCA)in alleviating abnormal gluconeogenesis and endoplasmic reticulum(ER)stress caused by type 2 diabetes mellitus(T2DM).In the in vivo study,8-week-old male C57BL/6J mice were fed with a high-fat and high-sugar diet and injected intraperitoneally with streptozotocin(STZ)to establish a T2DM model.LCA(5 and 10 mg·kg-1)was administered at an interval of 3 days for 3 weeks with metformin(MET,200 mg·kg-1)as a positive control drug.The animal experiment protocol was reviewed and approved by the Experimental Animal Ethics Committee of Beijing University of Chinese Medicine(approval number:BUCM-4-2021061701-2060).Human hepatoma cell line HepG2 was used as the experimental cell line for in vitro experiments.Sodium palmitate(SP)was used to induce the insulin resistance cell model and tunicamycin(TM)was applied to establish the ER stress cell model.Real-time quantitative polymerase chain reaction(RT-qPCR),enzyme-linked immunosorbent assay(ELISA)and Western blot(WB)were used to detect the mRNA and protein levels of gluconeogenesis and ER stress-related targets,respectively.Molecular docking and dynamics simulations were used to verify the interaction between LCA and key targets.The results showed that LCA inhibits gluconeogenesis by reducing phosphoenolpyruvate carboxykinase(PEPCK)and glucose-6-phosphatase(G6P)and increasing 6-phosphofructokinase-2/fructose-2,6-bisphosphatase 3(PFKFB3)at both the mRNA and protein levels,as well as suppressing the activity of pyruvate carboxylase(PC).Additionally,LCA alleviates ER stress by downregulating the transcription of eukaryotic initiation factor 2 subunit α(eIF2α),inositol-requiring enzyme 1α(IRE1α),X-box binding protein 1(XBP1),c-Jun N-terminal kinase 1(JNK1),and activating transcription factor 6α(ATF6α),inhibiting the transcription and protein expression of glucose-regulated protein 78(GRP78),and suppressing the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase(PERK).In conclusion,LCA alleviates abnormal gluconeogenesis and ER stress,thereby ameliorating the abnormal metabolism induced by T2DM.
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