| BackgroundAge-related macular degeneration(AMD),is a dominant irreversible blindness disease in elder population in the developed countries.It is generally divided into dry AMD and wet AMD.Wet AMD is characterized by the development of choroidal neovascularization(CNV)and the central vision impairment is the most frequent ending.At present,the treatment of wet AMD is mainly treated with anti VEGF drugs,but the visual acuity has not been significantly improved after anti VEGF treatment.Therefore,it is important to find new therapeutic targets.Liver X receptors(LXRs),members of lipid-activated transcription factors,belong to nuclear hormone receptor superfamily and have two isoforms(LXRα and LXRβ).Their target genes include ATP-binding cassette transporters A1(ABCA1)and ATP-binding cassette transporters G1(ABCG1).The primary function of LXRs is to regulate cholesterol homeostasis.On the other hand,activation of LXRs can reduce the expression of inflammatory factors in immune cells.In recent years,it has been found that chronic inflammation and metabolic disorders play a key role in the pathogenesis of AMD,but it is not clear that the mechanism of inflammation and its maintenance of inflammatory environment.As a nuclear receptor activated by oxidized sterols,LXR is involved in the regulation of lipid metabolism and inflammatory gene expression,which may be a new target for the treatment of AMD.PurposeTo investigate expressions of LXRs and their target genes ABCA1 and ABCG1 in the PBMCs in AMD patients.MethodsTwenty-three patients with exudative AMD and 23 age-matched healthy controls were enrolled in this study in Chongqing,China.Age,gender,other medical history and serum total cholesterol(TC),triglyceride(TG),high density lipoprotein cholesterol(HDL),low density lipoprotein cholesterol(LDL)levels were collected.Transcript levels of LXRs and their target genes in PBMCs were assessed with real-time PCR in 19 AMD patients and 19 controls.Toll-like receptors 4(TLR4)signaling including mediating factors interferon regulatory factor 3(IRF3),IFN-α,IFN-β and IFN-γ were measured with real-time PCR.PBMCs from 4 AMD patients and 4 controls were incubated with TO901317,a ligand of LXR,and then the m RNA expression of LXRs and their target genes were assessed.Data were analyzed by independent sample t test,nonparametric test,Pearson correlation analysis and ROC analysis.Results(1)There are no significant difference in age,gender,blood lipid level(including serum TC,TG,HDL and LDL)between AMD patients and control group.(2)Expressions of LXRα,LXRβ,ABCA1 and ABCG1 were significantly decreased in PBMCs of exudative AMD group in comparison to control group.The ROC analysis showed that the area under the ROC curve was 0.875 for LXRα(95% CI 0.7649-0.9858),0.900 for LXRβ(95% CI 0.8020-0.9986),0.878 for ABCA1(95% CI 0.7723-0.9840)and 0.905 for ABCG1(95% CI 0.8126-0.9990),respectively.(3)Expressions of TLR4,IRF3 and IFN-γ were significantly elevated in PBMCs of exudative AMD patients,while expressions of IFN-α and IFN-β were not changed.(4)Transcriptional responses of LXRα,ABCA1 and ABCG1 to the LXR agonist TO901317 was evident in both AMD and control subjects,while LXRβ was no changed.(5)Pearson correlation analysis showed that LXR was negatively correlated with TG,while LXR,ABCA1,ABCG1 had no correlation with TC,TG,HDL,LDL.Conclusions(1)LXRs and their target genes in PBMCs discriminated AMD patients from controls which may be nonspecific biomarkers for exudative AMD.Furthermore,LXRs might be a target for developing novel interventions for exudative AMD.(2)Given the fact that aberrant cholesterol metabolism and inflammation are involved in AMD,our data imply that LXRs may be an intersection of cholesterol metabolism disorder and inflammation. |
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