1. Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration.
- Author
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Tsai YT, Li Y, Ryu J, Su PY, Cheng CH, Wu WH, Li YS, Quinn PMJ, Leong KW, and Tsang SH
- Subjects
- Adolescent, Adult, Carboxylic Ester Hydrolases genetics, Cell Differentiation genetics, Cytokines metabolism, ErbB Receptors metabolism, Extracellular Matrix Proteins genetics, Extracellular Matrix Proteins metabolism, Humans, Inflammation metabolism, Lipid Metabolism, Macular Degeneration pathology, Middle Aged, Optic Disk Drusen congenital, Optic Disk Drusen metabolism, Proteomics, Proto-Oncogene Proteins c-akt metabolism, Retinal Pigment Epithelium pathology, Signal Transduction, Sp1 Transcription Factor metabolism, Transcription, Genetic, Unfolded Protein Response, Cholesterol metabolism, Macular Degeneration metabolism, Retinal Pigment Epithelium metabolism
- Abstract
Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. Here, we address this knowledge gap by comparing the proteomic profiles of induced pluripotent stem cell (iPSC)-derived RPEs (iRPE) from individuals with DHRD and their isogenic controls. Our analysis and follow-up studies elucidated the mechanism of lipid accumulation in DHRD iRPE cells. Specifically, we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export. CES1 knockdown or overexpression of EFEMP1
R345W , a variant of EGF-containing fibulin extracellular matrix protein 1 that is associated with DHRD and attenuated cholesterol efflux and led to lipid droplet accumulation. In iRPE cells, we also found that EFEMP1R345W has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1WT and may suppress CES1 expression via the downregulation of transcription factor SP1. Taken together, these results highlight the homeostatic role of cholesterol efflux in iRPE cells and identify CES1 as a mediator of cholesterol efflux in MD., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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