Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration

Autor: Chia-Hua Cheng, Stephen H. Tsang, Kam W. Leong, Joseph Ryu, Yong-Shi Li, Yi-Ting Tsai, Pei-Yin Su, Yao Li, Wen-Hsuan Wu, Peter M Quinn
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Adult
Proteomics
Adolescent
Transcription
Genetic
Sp1 Transcription Factor
Retinal Pigment Epithelium
030105 genetics & heredity
Drusen
Article
03 medical and health sciences
Extracellular matrix protein 1
chemistry.chemical_compound
Macular Degeneration
Downregulation and upregulation
Lipid droplet
Genetics
medicine
Humans
education
Genetics (clinical)
Inflammation
education.field_of_study
Extracellular Matrix Proteins
Retinal pigment epithelium
Optic Disk Drusen
Cell Differentiation
Macular degeneration
Middle Aged
medicine.disease
Lipid Metabolism
Fibulin
Cell biology
ErbB Receptors
030104 developmental biology
medicine.anatomical_structure
Cholesterol
chemistry
Cholesteryl ester
Unfolded Protein Response
Cytokines
Carboxylic Ester Hydrolases
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Am J Hum Genet
Popis: 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 EFEMP1(R345W) has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1(WT) 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.
Databáze: OpenAIRE
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