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Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2021 May 06; Vol. 108 (5), pp. 903-918. Date of Electronic Publication: 2021 Apr 27. - Publication Year :
- 2021
-
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 <superscript>R345W</superscript> , 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 EFEMP1 <superscript>R345W</superscript> has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1 <superscript>WT</superscript> 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.<br /> (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 108
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33909993
- Full Text :
- https://doi.org/10.1016/j.ajhg.2021.04.006