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

• Published in: Acta pharmaceutica Sinica. B Vol. 12; no. 6; pp. 2887 - 2904
• Main Authors: Xiao, Haiming, Sun, Xiaohong, Lin, Zeyuan, Yang, Yan, Zhang, Meng, Xu, Zhanchi, Liu, Peiqing, Liu, Zhongqiu, Huang, Heqing
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.06.2022; Elsevier
• Subjects: DDB2; Gentiopicroside; Glucose metabolism disorder; Insulin resistance; Lipid metabolism disorder; Original; PAQR3; PI3K/AKT; Ubiquitylation; Lipid metabolism disorder; Glucose metabolism disorder; Ubiquitylation; PAQR3; Insulin resistance; Gentiopicroside; PI3K/AKT; DDB2
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2021.12.023

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 PI3K/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 PI3K/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 PI3K catalytic subunit (P110α) to restore the PI3K/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. Gentiopicroside (GPS) decreased progestin and adipoQ receptor 3 (PAQR3) expression by promoting DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Importantly, GPS bound directly to PAQR3 and spatially inhibited the combination between PAQR3 and P110α to restore PI3K/AKT signaling. [Display omitted]