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

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

doi:10.1016/j.apsb.2021.12.023

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

a. Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
b. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China;
c. National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

基金项目:

This work was 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) and Guangdong Provincial Key Field and Program Project (No. 2020B1111100004, China).

详细信息

通讯作者:
Peiqing Liu,E-mail:liupq@mail.sysu.edu.cn

Zhongqiu Liu,E-mail:liuzq@gzucm.edu.cn

Heqing Huang,E-mail:huangheq@mail.sysu.edu.cn

中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383521004949/pdf?md5=b0efca1b70b92bd53c957b078a19608b&pid=1-s2.0-S2211383521004949-main.pdf
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出版历程
- 收稿日期: 2021-09-18
- 修回日期: 2021-11-08
- 录用日期: 2021-11-10
- 网络出版日期: 2023-03-17

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

Haiming Xiao^a,c,
Xiaohong Sun^a,
Zeyuan Lin^a,
Yan Yang^a,
Meng Zhang^a,c,
Zhanchi Xu^b,
Peiqing Liu^{a,c
, ,},
Zhongqiu Liu^{b
, ,},
Heqing Huang^{a,c
, ,}

a. Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
b. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China;
c. National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

Funds:

摘要

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 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 /
- Insulin resistance /
- PAQR3 /
- PI3K/AKT /
- DDB2 /
- Ubiquitylation /
- Glucose metabolism disorder /
- Lipid metabolism disorder
Abstract: 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 /
- Insulin resistance /
- PAQR3 /
- PI3K/AKT /
- DDB2 /
- Ubiquitylation /
- Glucose metabolism disorder /
- Lipid metabolism disorder

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参考文献(58)

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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

通讯作者:
Peiqing Liu,E-mail:liupq@mail.sysu.edu.cn

Zhongqiu Liu,E-mail:liuzq@gzucm.edu.cn

Heqing Huang,E-mail:huangheq@mail.sysu.edu.cn

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

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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

通讯作者: Peiqing Liu,E-mail:liupq@mail.sysu.edu.cn Zhongqiu Liu,E-mail:liuzq@gzucm.edu.cn Heqing Huang,E-mail:huangheq@mail.sysu.edu.cn

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出版历程

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

计量

出版历程

目录

通讯作者:
Peiqing Liu,E-mail:liupq@mail.sysu.edu.cn

Zhongqiu Liu,E-mail:liuzq@gzucm.edu.cn

Heqing Huang,E-mail:huangheq@mail.sysu.edu.cn