Liver X Receptor Agonist Ameliorates Amyloid β-induced Inflammation And Apoptosis In Retinal Pigment Epithelial Cells By Activating The Silent Information Regulator1 Signalling Cascade

PURPOSE: Amyloid β(Aβ)is a major component of drusen(a signature pathological change in early age-related macular degeneration)that causes retinal inflammation and apoptosis,and it is an important link in the pathological process of age-related macular degeneration(AMD).Research has shown that liver X receptor(LXR)plays an anti-inflammatory role in AMD by activating its target gene ABCA1.However,whether LXR activation prevents retinal pigment epithelial(RPE)cell apoptosis is still unclear.This study aimed to determine the role of the LXR-SIRT1 regulatory axis in RPE apoptosis and inflammation.METHODS: ARPE-19 cell lines were cultured in vitro,and peripheral blood from normal subjects and patients with wet age-related macular degeneration(AMD)were collected to extract PBMCs.The expression of SIRT1 in PBMCs and RPE cells was detected by real-time PCR.After pretreatment of hRPE and ARPE-19 cells with TO90(TO901317),a synthetic agonist of LXR,stimulation with Aβ1-40 or Aβ40-1 was performed.SIRT1 knockdown(iSIRT1)in hRPE and ARPE-19 cells was performed with lentiviral-mediated infection.The expression of P53 and NF-κB signalling pathway-associated proteins was examined by western blotting.RESULTS: Our data demonstrated that SIRT1 was downregulated in PBMCs of AMD patients as well as in Aβ–induced RPE apoptosis and inflammation.In both RPE cell lines,Aβ1-40 reduced SIRT1 signalling and its deacetylase activity,and increased acetylation and activation of the NF-κB and p53 signalling pathways,while TO90 counteracted deleterious effects.It was further confirmed by iSIRT1 that SIRT1 strongly participated in the protective effect of LXR on RPE cells.CONCLUSIONS:Activation of LXR rescues RPE cells from Aβ–induced apoptosis and inflammation through the activation of SIRT1.This study supports LXR as an effective target for alleviating Aβ-induced RPE cell injury and provides a theoretical basis for the development of related new drugs.