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

Min GAN; Qiaoya ZHOU; Meijing HONG; Xue LI; Hui PENG

doi:10.16016/j.1000-5404.202003092

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

Neurosciences | 更新时间：2026-01-09

- Liver X receptor agonist ameliorates amyloid β-induced inflammation and apoptosis in retinal pigment epithelial cells by activating SIRT1 signaling cascade
- Journal of Third Military Medical University Vol. 42, Issue 14, Pages: 1398-1406(2020)
- 作者机构：
  
  400016 重庆，重庆医科大学附属第一医院眼科，眼科学重庆市市级重点实验室，重庆市眼科研究所
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81670881)
- DOI：10.16016/j.1000-5404.202003092
  CLC： R329.25;R774.5;R977.6
- Received：10 March 2020，
  
  Revised：2020-04-30，
  
  Published：30 July 2020
- 稿件说明：
移动端阅览
Min GAN, Qiaoya ZHOU, Meijing HONG, et al. Liver X receptor agonist ameliorates amyloid β-induced inflammation and apoptosis in retinal pigment epithelial cells by activating SIRT1 signaling cascade[J]. Journal of Third Military Medical University, 2020, 42(14): 1398-1406.
DOI：

Min GAN, Qiaoya ZHOU, Meijing HONG, et al. Liver X receptor agonist ameliorates amyloid β-induced inflammation and apoptosis in retinal pigment epithelial cells by activating SIRT1 signaling cascade[J]. Journal of Third Military Medical University, 2020, 42(14): 1398-1406. DOI： 10.16016/j.1000-5404.202003092.

摘要

目的

探讨LXR-SIRT1调控轴在淀粉样β(amyloidβ

Aβ)诱导的视网膜上皮(retinal pigment epithelial

RPE)细胞炎症和凋亡中的作用。

方法

体外培养ARPE-19细胞系，收集湿性年龄相关性黄斑变性(age-related macular degeneration，AMD)患者和正常受试者的人外周血单个核细胞(human peripheral blood mononuclear cell

PBMC)并检测其中沉默信息调节因子1(silencing information regulator 1

SIRT1)的mRNA表达。用1.0、5.0 μmol/L的Aβ1-40和5.0 μmol/L Aβ40-1处理ARPE-19细胞24 h，Real-time PCR检测SIRT1、IL-1β、p21在ARPE-19细胞中的表达，探讨Aβ对ARPE-19细胞炎症、凋亡的影响。用5.0 μmol/L Aβ1-40和5.0 μmol/L TO90处理ARPE-19细胞，Western blot检测SIRT1、LXRα、ace-NF-κB、NF-κB、ace-p53、p53、p21的表达，研究Aβ1-40刺激及TO90预处理对SIRT1信号级联的影响。在敲低SIRT1后，Western blot检测NF-κB和p53信号通路的表达，进一步验证TO90对SIRT1信号级联的调控作用。

结果

SIRT1在湿性AMD患者的PBMC中明显下调(

0.01)。Aβ1-40刺激ARPE-19细胞后，SIRT1在mRNA及蛋白水平明显下调(

0.05)，p21在mRNA及蛋白水平明显上调(

0.05)，IL-1β在基因水平明显上调(

0.05)，ace-NF-κB、NF-κB、ace-p53、p53在蛋白水平显著上调(

0.05)，而TO90预处理则可逆转Aβ1-40对这些因子的调节(

0.05)。SIRT1敲低后，TO90对ace-NF-κB、NF-κB、ace-p53、p53上调的逆转作用显著下降(

0.05)。

结论

LXR激动剂通过激活SIRT1信号级联改善Aβ诱导的ARPE-19细胞炎症及凋亡反应。

Abstract

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 (

0.05). Aβ stimulation of ARPE-19 cells caused obvious downregulation of SIRT1 (

0.05) and upregulation of p21 at both the mRNA and protein levels (

0.05)

upregulation of IL-1β at the mRNA level (

0.05)

and upregulation of ace-NF-κB

NF-κB

ace-p53

and p53 at the protein level (

0.05); TO90 pret

reatment effectively abolished the effects of Aβ on these factors (

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 (

0.05).

Conclusion

LXR agonists improve Aβ-induced inflammation and apoptosis in ARPE-19 cells by activating the SIRT1 signaling cascade.

关键词

Keywords

references

WONG W L, SU X Y, LI X, et al . Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis[J ] . Lancet Glob Health, 2014, 2(2): e106-e116. DOI: 10.1016/S2214-109X(13)70145-1.

FERRIS F L 3rd, WILKINSON C P, BIRD A, et al . Clinical classification of age-related macular degeneration[J ] . Ophthalmology, 2013, 120(4): 844-851. DOI: 10.1016/j.ophtha.2012.10.036.

ANDERSON D H, TALAGA K C, RIVEST A J, et al . Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration[J ] . Exp Eye Res, 2004, 78(2): 243-256. DOI: 10.1016/j.exer.2003.10.011.

YE Z, HE S Z, LI Z H. Effect of Aβ protein on inhibiting proliferation and promoting apoptosis of retinal pigment epithelial cells[J]. Int J Ophthalmol, 2018, 11(6): 929-934. DOI: 10.18240/ijo.2018.06.06.

WANG B, TONTONOZ P. Liver X receptors in lipid signalling and membrane homeostasis[J]. Nat Rev Endocrinol, 2018, 14(8): 452-463. DOI: 10.1038/s41574-018-0037-x.

CEROI A, DELETTRE F A, MAROTEL C, et al . The anti-inflammatory effects of platelet-derived microparticles in human plasmacytoid dendritic cells involve liver X receptor activation[J ] .Haematologica, 2016, 101(3): e72-e76. DOI: 10.3324/haematol.2015.135459.

CAO E Y, LINDGREN A, MARTINSSON S, et al . Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252, 623) to lymphocytes and enhances immunomodulation[J ] . J Control Release, 2019, 296: 29-39. DOI: 10.1016/j.jconrel.2019.01.002.

ZHENG W C, REEM R E, OMAROVA S, et al . Spatial distribution of the pathways of cholesterol homeostasis in human Retina[J ] . PLoS ONE, 2012, 7(5): e37926. DOI: 10.1371/journal.pone.0037926.

YANG H X, ZHENG S J, QIU Y G, et al . Activation of liver X receptor alleviates ocular inflammation in experimental autoimmune uveitis[J ] . Invest Ophthalmol Vis Sci, 2014, 55(4): 2795-2804. DOI: 10.1167/iovs.13-13323.

ZHENG S J, YANG H X, CHEN Z H, et al . Activation of liver X receptor protects inner retinal damage induced by N-methyl-D-aspartate[J ] . Invest Ophthalmol Vis Sci, 2015, 56(2): 1168-1180. DOI: 10.1167/iovs.14-15612.

DAI B L, LEI C Y, LIN R, et al . Activation of liver X receptor α protects amyloid β1-40 induced inflammatory and senescent responses in human retinal pigment epithelial cells[J ] . Inflamm Res, 2017, 66(6): 523-534. DOI: 10.1007/s00011-017-1036-4.

TSENG R C, WANG Y C. SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae))[J]. Atlas Genet Cytogenet Oncol Haematol, 2010, 14(12): 1152. DOI: 10.4267/2042/44919.

HAN X, CUI Z Y, SONG J, et al . Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner[J ] . Chem Biol Interact, 2019, 311: 108794. DOI: 10.1016/j.cbi.2019.108794.

HAMMER S S, BELI E, KADY N, et al . The mechanism of diabetic retinopathy pathogenesis unifying key lipid regulators, sirtuin 1 and liver X receptor[J ] . EBioMedicine, 2017, 22: 181-190. DOI: 10.1016/j.ebiom.2017.07.008.

KURJI K H, CUI J Z, LIN T, et al . Microarray analysis identifies changes in inflammatory gene expression in response to amyloid-beta stimulation of cultured human retinal pigment epithelial cells[J ] . Invest Ophthalmol Vis Sci, 2010, 51(2): 1151-1163. DOI: 10.1167/iovs.09-3622.

LEI C Y, LIN R, WANG J M, et al . Amelioration of amyloid β-induced retinal inflammatory responses by a LXR agonist TO901317 is associated with inhibition of the NF-κB signaling and NLRP3 inflammasome[J ] . Neuroscience, 2017, 360: 48-60. DOI: 10.1016/j.neuroscience.2017.07.053.

SELKOE D J, PODLISNY M B, JOACHIM C L, et al . Beta-amyloid precursor protein of Alz heimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues[J ] . Proc Natl Acad Sci USA, 1988, 85(19): 7341-7345. DOI: 10.1073/pnas.85.19.7341.

DE MEYER G R, DE CLEEN D M, COOPER S, et al . Platelet phagocytosis and processing of beta-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis[J ] . Circ Res, 2002, 90(11): 1197-1204. DOI: 10.1161/01.res.0000020017.84398.61.

LIU C Q, CAO L N, YANG S, et al . Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration[J ] . Int J Mol Med, 2015, 35(1): 169-176. DOI: 10.3892/ijmm.2014.1993.

CARRERO I, GONZALO M R, MARTIN B, et al . Oligomers of β-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1β, tumour necrosis factor-α, and a nuclear factor κ-B mechanism in the rat brain[J ] . Exp Neurol, 2012, 236(2): 215-227. DOI: 10.1016/j.expneurol.2012.05.004.

MÜLLER T, MEYER H E, EGENSPERGER R, et al . The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer's disease[J ] . Prog Neurobiol, 2008, 85(4): 393-406. DOI: 10.1016/j.pneur obio.2008.05.002.

SAMUEL W, JAWORSKI C, POSTNIKOVA O A, et al . Appropriately differentiated ARPE-19 cells regain phenotype and gene expression profiles similar to those of native RPE cells[J ] . Mol Vis, 2017, 23: 60-89.

BRUBAN J, GLOTIN A L, DINET V, et al . Amyloid-beta(1-42) alters structure and function of retinal pigmented epithelial cells[J ] . Aging Cell, 2009, 8(2): 162-177. DOI: 10.1111/j.1474-9726.2009.00456.x.

MASUDA N, TSUJINAKA H, HIRAI H, et al . Effects of concentration of amyloid β (Aβ) on viability of cultured retinal pigment epithelial cells[J ] . BMC Ophthalmol, 2019, 19(1): 70. DOI: 10.1186/s12886-019-1076-3.

HALLE A, HORNUNG V, PETZOLD G C, et al . The NALP3 inflammasome is involved in the innate immune response to amyloid-beta[J ] . Nat Immunol, 2008, 9(8): 857-865. DOI: 10.1038/ni.1636.

KAARNIRANTA K, SALMINEN A. Age-related macular degeneration: activation of innate immunity system via pattern recognition receptors[J ] . J Mol Med, 2009, 87(2): 117-123. DOI: 10.1007/s00109-008-0418-z.

HISCOTT J, MAROIS J, GAROUFALIS J, et al . Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop[J ] . Mol Cell Biol, 1993, 13(10): 6231-6240. DOI: 10.1128/mcb.13.10.6231.

BALAIYA S, KHETPAL V, CHALAM K V. Hypoxia initiates sirtuin1-mediated vascular endothelial growth factor activation in choroidal endothelial cells through hypoxia inducible factor-2α[J]. Mol Vis, 2012, 18: 114-120.

ZHUGE C C, XU J Y, ZHANG J F, et al . Fullerenol protects retinal pigment epithelial cells from oxidative stress-induced premature senescence via activating SIRT1[J ] . Invest OphthalmolVis Sci, 2014, 55(7): 4628-4638. DOI: 10.1167/iovs.13-13732..

LI X L, ZHANG S W, BLANDER G, et al . SIRT1 deacetylates and positively regulates the nuclear receptor LXR[J ] . Mol Cell, 2007, 28(1): 91-106. DOI: 10.1016/j.molcel.2007.07.032.

ESCOLÀ-GIL J C, JULVE J, LLAVERIAS G, et al . Resveratrol administration or SIRT1 overexpression does not increase LXR signaling and macrophage-to-feces reverse cholesterol transport in vivo[J ] . Transl Res, 2013, 161(2): 110-117. DOI: 10.1016/j.trsl.2012.10.008.

PHILLIPS M C. Molecular mechanisms of cellular cholesterol efflux[J]. J Biol Chem, 2014, 289(35): 24020-24029. DOI: 10.1074/jbc.R114.583658.

ITO A, HONG C, RONG X, et al . LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling[J ] . Elife, 2015, 4: e08009. DOI: 10.7554/eLife.08009.

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