A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor

Aya Iriyama, Ryoji Fujiki, Yuji Inoue, Hidenori Takahashi, Yasuhiro Tamaki, Shinichiro Takezawa, Kenichi Takeyama, Woo Dong Jang, Shigeaki Kato, Yasuo Yanagi

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Lipofuscin contains fluorophores, which represent a biomarker for cellular aging. Although it remains unsubstantiated clinically, experimental results support that the accumulation of lipofuscin is related to an increased risk of choroidal neovascularization due to age-related macular degeneration, a leading cause of legal blindness. Here, we report that a major lipofuscin component, A2E, activates the retinoic acid receptor (RAR). In vitro experiments using luciferase reporter assay, competitional binding assay, analysis of target genes, and chromatin immunoprecipitation (ChIP) assay strongly suggest that A2E is a bona fide ligand for RAR and induces sustained activation of RAR target genes. A2E-induced vascular endothelial growth factor (VEGF) expression in a human retinal pigment epithelial cell line (ARPE-19) and RAR antagonist blocked the up-regulation of VEGF. The conditioned medium of A2E-treated ARPE-19 cells induced tube formation in human umbilical vascular endothelial cells, which was blocked by the RAR antagonist and anti-VEGF antibody. These results suggest that A2E accumulation results in the phenotypic alteration of retinal pigment epithelial cells, predisposing the environment to choroidal neovascularization development. This is mediated through the agonistic function of A2E, at least in part. The results of this study provide a novel potential therapeutic target for this incurable condition.

Original languageEnglish
Pages (from-to)11947-11953
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number18
DOIs
Publication statusPublished - 2008 May 2

Fingerprint

Lipofuscin
Retinoic Acid Receptors
Retinal Pigments
Pigments
Epithelial Cells
Ligands
Vascular Endothelial Growth Factor A
Assays
Choroidal Neovascularization
Genes
Umbilicus
Fluorophores
Chromatin Immunoprecipitation
Cell Aging
Endothelial cells
Macular Degeneration
Biomarkers
Blindness
Conditioned Culture Medium
Luciferases

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Iriyama, A., Fujiki, R., Inoue, Y., Takahashi, H., Tamaki, Y., Takezawa, S., ... Yanagi, Y. (2008). A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor. Journal of Biological Chemistry, 283(18), 11947-11953. https://doi.org/10.1074/jbc.M708989200
Iriyama, Aya ; Fujiki, Ryoji ; Inoue, Yuji ; Takahashi, Hidenori ; Tamaki, Yasuhiro ; Takezawa, Shinichiro ; Takeyama, Kenichi ; Jang, Woo Dong ; Kato, Shigeaki ; Yanagi, Yasuo. / A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 18. pp. 11947-11953.
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Iriyama, A, Fujiki, R, Inoue, Y, Takahashi, H, Tamaki, Y, Takezawa, S, Takeyama, K, Jang, WD, Kato, S & Yanagi, Y 2008, 'A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor', Journal of Biological Chemistry, vol. 283, no. 18, pp. 11947-11953. https://doi.org/10.1074/jbc.M708989200

A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor. / Iriyama, Aya; Fujiki, Ryoji; Inoue, Yuji; Takahashi, Hidenori; Tamaki, Yasuhiro; Takezawa, Shinichiro; Takeyama, Kenichi; Jang, Woo Dong; Kato, Shigeaki; Yanagi, Yasuo.

In: Journal of Biological Chemistry, Vol. 283, No. 18, 02.05.2008, p. 11947-11953.

Research output: Contribution to journalArticle

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T1 - A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor

AU - Iriyama, Aya

AU - Fujiki, Ryoji

AU - Inoue, Yuji

AU - Takahashi, Hidenori

AU - Tamaki, Yasuhiro

AU - Takezawa, Shinichiro

AU - Takeyama, Kenichi

AU - Jang, Woo Dong

AU - Kato, Shigeaki

AU - Yanagi, Yasuo

PY - 2008/5/2

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N2 - Lipofuscin contains fluorophores, which represent a biomarker for cellular aging. Although it remains unsubstantiated clinically, experimental results support that the accumulation of lipofuscin is related to an increased risk of choroidal neovascularization due to age-related macular degeneration, a leading cause of legal blindness. Here, we report that a major lipofuscin component, A2E, activates the retinoic acid receptor (RAR). In vitro experiments using luciferase reporter assay, competitional binding assay, analysis of target genes, and chromatin immunoprecipitation (ChIP) assay strongly suggest that A2E is a bona fide ligand for RAR and induces sustained activation of RAR target genes. A2E-induced vascular endothelial growth factor (VEGF) expression in a human retinal pigment epithelial cell line (ARPE-19) and RAR antagonist blocked the up-regulation of VEGF. The conditioned medium of A2E-treated ARPE-19 cells induced tube formation in human umbilical vascular endothelial cells, which was blocked by the RAR antagonist and anti-VEGF antibody. These results suggest that A2E accumulation results in the phenotypic alteration of retinal pigment epithelial cells, predisposing the environment to choroidal neovascularization development. This is mediated through the agonistic function of A2E, at least in part. The results of this study provide a novel potential therapeutic target for this incurable condition.

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