Liver X receptor agonist ameliorates amyloid β-induced inflammation and apoptosis in retinal pigment epithelial cells by activating SIRT1 signaling cascade

• Main Authors: GAN Min, ZHOU Qiaoya, HONG Meijing, LI Xue, PENG Hui
• Format: Article
• Language: zho
• Published: Editorial Office of Journal of Third Military Medical University 2020-07-01
• Series: Di-san junyi daxue xuebao
• Subjects: retinal pigment epithelium; liver x receptor; silencing information regulator 1; β-amyloid; age-related macular degeneration
• Online Access: http://aammt.tmmu.edu.cn/Upload/rhtml/202003092.htm

Objective To investigate the role of liver X receptor (LXR)-SIRT1 regulatory axis in inflammation and apoptosis of retinal pigment epithelial (RPE) cells induced by β-amyloid (Aβ). Methods Human peripheral blood mononuclear cells (PBMCs) were collected from patients with wet age-related macular degeneration (AMD) and normal subjects for detection of SIRT1 mRNA expression. And then, human RPE cell line ARPE-19 stimulated with 1.0, 5.0 μmol/L Aβ1-40 or 5.0 μmol/L Aβ40-1 was examined for expression of SIRT1, IL-1β and p21 using real-time PCR to investigate the effects of Aβ on cell inflammation and apoptosis; Subsequently, the expression levels of SIRT1, LXRα, ace-NF-κB, NF-κB, ace-p53, p53, and p21 proteins in ARPE-19 cells treated with 5.0 μmol/L Aβ1-40, 5.0 μmol/L TO90, or both were detected using Western blotting to analyze the effect of Aβ1-40 stimulation and TO90 pretreatment on SIRT1 signaling cascade. Finally, after knocking down SIRT1, the expression of NF-κB and p53 signaling pathways was detected by Western blot analysis to further verify the regulatory effect of TO90 on the SIRT1 signaling cascade. Results SIRT1 was significantly down-regulated in the PBMCs of patients with wet AMD (P < 0.05). Aβ stimulation of ARPE-19 cells caused obvious downregulation of SIRT1 (P < 0.05) and upregulation of p21 at both the mRNA and protein levels (P < 0.05), upregulation of IL-1β at the mRNA level (P < 0.05), and upregulation of ace-NF-κB, NF-κB, ace-p53, and p53 at the protein level (P < 0.05); TO90 pretreatment effectively abolished the effects of Aβ on these factors (P < 0.05). After SIRT1 knockdown, the reverse effect of TO90 on the upregulation of ace-NF-κB, NF-κB, ace-p53, and p53 was significantly reduced (P < 0.05). Conclusion LXR agonists improve Aβ-induced inflammation and apoptosis in ARPE-19 cells by activating the SIRT1 signaling cascade.