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

Tsai, Yi‐Ting; Li, Yao; Ryu, Joseph; Su, Pei-Yin; Cheng, Chia-Hua; Wu, W. D.; Li, Yong-Shi; Quinn, Peter M J; Leong, Kam W.; Tsang, Stephen H.

doi:10.1016/j.ajhg.2021.04.006

Cited by 14 publications

(11 citation statements)

References 70 publications

(86 reference statements)

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“…The cholesterol metabolism in the retina is a complex process and the current results warrants further investigations using retinal cells such as RPE, neural retinal and Muller cells. 53 Our results showed that compared to early AMD, systemic cholesterol efflux capacity was lower in tAMD patients. This phenomenon is not easily explained, but a previous study also showed that cholesterol efflux capacity in nAMD was not different from that in controls.…”

Section: Cholesterol Efflux and Early Amd And Pcvmentioning

confidence: 49%

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Serum Cholesterol Efflux Capacity in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Yanagi

Ahamed

et al. 2022

Ophthalmology Science

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Section: Cholesterol Efflux and Early Amd And Pcvmentioning

confidence: 49%

“…The cholesterol metabolism in the retina is a complex process, and the current results warrant further investigation using retinal cells such as RPE cells, neural retinal cells, and Müller cells. 53 …”

Section: Discussionmentioning

confidence: 99%

Serum Cholesterol Efflux Capacity in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Yanagi

Ahamed

et al. 2022

Ophthalmology Science

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“…Intracellular lipid accumulation is toxic for cells and the formation of lipid-loaded drusen is a hallmark of AMD [ 6 , 17 , 35 ]. GWAS identified polymorphisms in genes related to the cholesterol pathway that are associated with AMD risk.…”

Section: Resultsmentioning

confidence: 99%

“…Such RPE cells exhibited a metabolic shift from lipid oxidation to glycolysis, resulting not only in reduced glucose availability for photoreceptors with detrimental effects for their survival but also in an increase of intracellular lipids, which is harmful for RPE function and survival [ 17 , 51 , 52 ]. Therefore, reduction of intracellular lipotoxicity by enhancing lipid efflux is suggested to be a promising approach to delay AMD progression [ 17 , 35 ]. We show that stimulating ABCA1 expression using an LXR agonist significantly increased cholesterol efflux ( Figure 5 E) under hypoxia and reduced intracellular lipid accumulation ( Figure 5 F), demonstrating that a treatment paradigm with an LXR agonist could be a promising approach.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE

Peters

Ebner

Atac

et al. 2022

IJMS

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Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD.

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EFEMP1 rare variants cause familial juvenile‐onset open‐angle glaucoma

et al. 2021

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Juvenile open‐angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co‐segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early‐onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.

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

Cited by 14 publications

References 70 publications

Serum Cholesterol Efflux Capacity in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Serum Cholesterol Efflux Capacity in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE

EFEMP1 rare variants cause familial juvenile‐onset open‐angle glaucoma

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