SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR.
10.1016/j.apsb.2022.08.019
- Author:
Shuang CUI
1
;
Huijian HU
1
;
An CHEN
1
;
Ming CUI
1
;
Xiaojie PAN
1
;
Pengfei ZHANG
1
;
Guangji WANG
1
;
Hong WANG
1
;
Haiping HAO
1
Author Information
1. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
- Publication Type:Journal Article
- Keywords:
Acetylation;
Combinatorial drugs;
Degradation;
FXR;
Nonalcoholic steatohepatitis;
Nuclear receptor;
Nucleocytoplasmic shuttling;
Phosphorylation
- From:
Acta Pharmaceutica Sinica B
2023;13(2):559-576
- CountryChina
- Language:English
-
Abstract:
Farnesoid X receptor (FXR) is widely accepted as a promising target for various liver diseases; however, panels of ligands in drug development show limited clinical benefits, without a clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury, which represents the major culprit that limits the clinical benefits of FXR agonists against liver diseases. Upon inflammatory and apoptotic stimulation, enhanced FXR acetylation at K217, closed to the nuclear location signal, blocks its recognition by importin KPNA3, thereby preventing its nuclear import. Concomitantly, reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1, and thereby facilitating FXR export to the cytosol. Acetylation governs nucleocytoplasmic shuttling of FXR, resulting in enhanced cytosolic retention of FXR that is amenable to degradation by CHIP. SIRT1 activators reduce FXR acetylation and prevent its cytosolic degradation. More importantly, SIRT1 activators synergize with FXR agonists in combating acute and chronic liver injuries. In conclusion, these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.
