SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

• DOI: 10.1016/j.apsb.2022.08.019
• Publication Date: 2022-08-28T01:38:57Z
• Authors: Shuang Cui; Huijian Hu; An Chen; Ming Cui; Xiaojie Pan; Pengfei Zhang; Guangji Wang; Hong Wang; Haiping Hao
• Keywords: Farnesoid X receptor; Nuclear export signal; Hepatoprotection

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 clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling then enhances degradation by the cytosolic E3 ligase CHIP under conditions injury, which represents major culprit limits benefits agonists against diseases. Upon inflammatory apoptotic stimulation, enhanced at K217, closed to nuclear location signal, blocks its recognition importin KPNA3, thereby preventing import. Concomitantly, reduced phosphorylation T442 within export signals promotes exportin CRM1, facilitating cytosol. Acetylation governs FXR, resulting retention amenable CHIP. SIRT1 activators reduce prevent degradation. More importantly, synergize with combating acute chronic injuries. In conclusion, these findings innovate strategy develop therapeutics diseases combining agonists.