The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells
Open accessAbstract
Proteins involved in cholesterol trafficking are known to contribute to the pathogenesis of atherosclerosis and Alzheimer's disease. Allelic variants in the cholesterol transporters apolipoprotein E and ATP-binding cassette protein A1 (ABCA1) have recently been associated with susceptibility to age-related macular degeneration (AMD). Histopathological analyses of eyes with AMD demonstrate the presence of cholesterol and cholesteryl ester deposits beneath the retinal pigment epithelium (RPE), implicating abnormal cholesterol trafficking in disease progression. Here, we show that A2E, a quaternary amine and retinoid by-product of the visual cycle, causes the accumulation of free and esterified cholesterol in RPE cells. The mechanism involves neither generalized alterations in late endosomal/lysosomal pH nor a direct inhibition of acid lipase activity. Rather, A2E prevents cholesterol efflux from these organelles, which in turn indirectly inhibits acid lipase, leading to a subsequent accumulation of cholesteryl esters. Transcriptional activation of the ABCA1 cholesterol transporter by agonists of the liver X receptor/peroxisome proliferator-activated receptor pathway relieves the A2E-induced block on cholesterol efflux and restores cholesterol homeostasis in RPE cells. Our data also demonstrate that A2E, which is a cone-shaped lipid, increases the chemical activity and displacement of cholesterol from model membranes, providing a biophysical mechanism for cholesterol sequestration in A2E-loaded cells. Although endogenously produced A2E in the RPE has been associated with macular degeneration, the precise mechanisms are unclear. Our results provide direct evidence that A2E causes aberrant cholesterol metabolism in RPE cells which could likely contribute to AMD progression.
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In Abca4−/− mice, lipofuscin bisretinoids such as A2E trap cholesterol and the anionic lipid bis-monoacylglycerophosphate (BMP) within RPE lysosomes.
“In Abca4−/− mice, lipofuscin bisretinoids such as A2E trap cholesterol and the anionic lipid bis-monoacylglycerophosphate (BMP) within RPE lysosomes (Lakkaraju et al., 2007; Toops et al., 2015).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Lakkaraju et al., 2007
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- Authors
- Lakkaraju, A., Finnemann, S. C., & Rodriguez-Boulan, E.
- Affiliations
- *Margaret M. Dyson Vision Research Institute, Department of Ophthalmology,
- Cornell University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-06-26
- Volume
- 104
- Issue
- 26
- Pages
- 11026-11031
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1904145
- OpenAlex
- W2030787754
- Cited by
- 162
- References
- 41
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 15 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 12 · 2019: 7 · 2018: 6 · 2017: 14 · 2016: 4 · 2015: 7 · 2014: 19 · 2013: 3 · 2012: 8
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Update notices
- correction (2008-08-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research to Prevent Blindness
- Dyson Foundation
- National Institutes of Health (EY08538)
- National Eye Institute (EY08538, R01EY013295, EY-13295, R01EY008538, F32EY015363)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- A2E, lipofuscin, retinal pigment epithelium, cholesterol metabolism, cholesterol efflux, cholesterol esters, acid lipase, ABCA1, liver X receptor, peroxisome proliferator-activated receptors, age-related macular degeneration, cholesterol transport, lysosomal pH
- MeSH terms
- Cell Line, Cholesterol, Cholesterol Esters, Humans, Lipase, Lipofuscin, Macular Degeneration, Pigment Epithelium of Eye, Pyridinium Compounds, Retina, Retinoids, ATP-Binding Cassette Transporters, Lipid Metabolism, ATP Binding Cassette Transporter 1
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