Chinese medicine pentacyclic triterpene celastrol ameliorates inflammation, metabolic dysfunctions and insulin resistance in diet-induced obesity via covalently modifying endoplasmic reticulum chaperone GRP78

Professor Rong, Jianhui   (Principal Investigator (PI))

Professor Li Xuechen   (Co-Investigator)

Professor Wang Yu   (Co-Investigator)

Dr Xia Zhengyuan   (Co-Investigator)

42

2020-01-01

2023-06-30

928117

Chinese medicine pentacyclic triterpene celastrol ameliorates inflammation, metabolic dysfunctions and insulin resistance in diet-induced obesity via covalently modifying endoplasmic reticulum chaperone GRP78

Chaperone GRP78, Chinese medicine celastrol, ER stress, Molecular mechanism, Obesity

Traditional Chinese Medicine (basic)Pharmacology/Toxicology

Biology and Medicine (M)

17119619

General Research Fund (GRF)

2019

Completed

1 To elucidate the formation of celastrol-GRP78 conjugate and subsequent effects on chaperone activity and unfolded protein degradation. GRP78 senses unfolded proteins and activates ER stress signalling pathways. We for the first time discovered the formation of covalent celastrol-GRP78 conjugate. Covalent celastrol-GRP78 conjugation may help the control of unfolded protein response against lipidotoxicity. We will determine the molecular basis of celastrol-GRP78 conjugation and the potential effects on the chaperone activity and unfolded protein degradation. 2 To determine the effects of celastrol-GRP78 conjugation on unfolded protein responses, ER stress sensing and ER-phagy. Obesity promotes the accumulation of unfolded proteins, regulates GRP78 chaperone activity and thereby induces ER stress. Our pilot results demonstrated that celastrol attenuated palmitate-induced activation of ATF6, IRE1α and PERK. Thus, the present study will determine whether celastrol-GRP78 conjugation could not only prevent the activation of ER stress signalling pathways but also activate ER-phagy towards the resolution of unfolded proteins. 3 To discover the structure-activity relationship towards the development of specific GRP78 inhibitors. Celastrol may bind several different protein targets. Thus, this project was designed to determine whether celastrol primarily targets GRP78 against obesity and discover the structural elements for specific binding to GRP78. We performed virtual screening and developed a synthetic procedure for preparing 6-substituted celastrol derivatives. We will further determine celastrol derivatives against ER stress, inflammation, lipid metabolism and insulin resistance.