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

• DOI: 10.1016/j.apsb.2021.12.023
• Publication Date: 2022-01-06T10:39:49Z
• Authors: Haiming Xiao; Xiaohong Sun; Zeyuan Lin; Yan Yang; Meng Zhang; Zhanchi Xu; Peiqing Liu; Zhongqiu Liu; Heqing Huang
• Keywords: Gentiopicroside; PI3K/AKT; 0303 health sciences; 03 medical and health sciences; Ubiquitylation; DDB2; Insulin resistance; Original Article; Therapeutics. Pharmacology; RM1-950; PAQR3; 3. Good health

The obstruction of post-insulin receptor signaling is the main mechanism insulin-resistant diabetes. Progestin and adipoQ 3 (PAQR3), a key regulator inflammation metabolism, can negatively regulate PI3K/AKT pathway. Here, we report that gentiopicroside (GPS), bioactive secoiridoid glycoside Gentiana manshurica Kitagawa, decreased lipid synthesis increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism streptozotocin (STZ) high-fat diet (HFD)-induced diabetic mice. Our findings revealed promoted activation axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results surface plasmon resonance (SPR), microscale thermophoresis (MST) thermal shift assay (TSA) indicated directly binds to PAQR3. Results molecular docking cellular (CETSA) bound amino acids NH2-terminus including Leu40, Asp42, Glu69, Tyr125 Ser129, spatially inhibited interaction between PI3K catalytic subunit (P110α) restore In summary, our study identified GPS, which inhibits expression targets insulin pathway, as potential drug candidate for treatment