Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism  

作　　者：Haiming Xiao Xiaohong Sun Zeyuan Lin Yan Yang Meng Zhang Zhanchi Xu Peiqing Liu Zhongqiu Liu Heqing Huang 

机构地区：[1]Laboratory of Pharmacology&Toxicology,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]School of Pharmaceutical Sciences,Guangzhou University of Chinese Medicine,Guangzhou 510006,China [3]National and Local United Engineering Lab of Druggability and New Drugs Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第6期2887-2904,共18页药学学报（英文版）

基　　金：supported by research grants from the National Natural Science Foundation of China (No.81770816 and 81973375);the Key Project of Natural Science Foundation of Guangdong Province,China (No.2017A030311036);Seed Program of Guangdong Province (No.2017B090903004,China);Guangdong Provincial Key Field and Program Project (No.2020B1111100004,China)。

摘　　要：The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.

关 键 词：GENTIOPICROSIDE Insulin resistance PAQR3 PI3K/AKT DDB2 UBIQUITYLATION Glucose metabolism disorder Lipid metabolism disorder 

分 类 号：R587.1[医药卫生—内分泌]