Cholesterol and age-related macular degeneration: is there a link?

Leeuwen, Redmer van; Klaver, Caroline C.W.; Vingerling, Johannes R.; Hofman, Albert; Duijn, Cornelia M. van; Stricker, Bruno H.; Jong, Paulus T. V. M. de

doi:10.1016/j.ajo.2003.09.015

Cited by 106 publications

(79 citation statements)

References 6 publications

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“…Although it is difficult to draw any mechanistic conclusions from this correlation, these results do support the validity and accuracy of our SNP typing methodology. These results also suggest a serum cholesterol-independent disease pathway in AMD [van Leeuwen et al, 2004].…”

Section: Discussionsupporting

confidence: 56%

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Bojanowski

Shen

Chew

et al. 2006

Environ and Mol Mutagen

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Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among the elderly in Western countries. Genetic factors, age, cigarette smoking, nutrition, and exposure to light have been identified as AMD risk factors. In this study, we investigated the association between ApoE C112R/R158C single nucleotide polymorphisms (which determine the E2, E3, and E4 isoforms) and age-related macular degeneration (AMD), and the mechanism underlying the association. Genomic DNA was extracted from 133 clinically screened controls, 94 volunteers with a younger mean age, 120 patients with advanced AMD, and 40 archived ocular AMD slides for single nucleotide polymorphism typing. The effects of recombinant ApoE isoforms on CCL2 (a chemokine), CX3CR1 (a chemokine receptor), and VEGF (a cytokine) expression in cultured human retinal pigment epithelium (RPE) cells were tested and serum cholesterol profiles of the clinically screened subjects were analyzed. ApoE112R (E4) distribution differed significantly between AMD patients and controls. ApoE112R allele frequency was 10.9% in the AMD group when compared with 16.5% in the younger controls and 18.8% in the clinically screened controls. The pathologically diagnosed archived AMD cases had the lowest allele frequency of 5%. No significant differences in ApoE158C (E2) distribution were observed among the groups. A meta-analysis of 8 cohorts including 4,289 subjects showed a strong association between AMD and 112R, but not 158C. In vitro studies found that recombinant ApoE suppresses CCL2 and VEGF expression in RPE cells. However, the E4 isoform showed more suppression than E3 in both cases. These results further confirm the association between ApoE112R and a decreased risk of AMD development. The underlying mechanisms may involve differential regulation of both CCL2 and VEGF by the ApoE isoforms.

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Section: Discussionsupporting

confidence: 56%

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Bojanowski

Shen

Chew

et al. 2006

Environ and Mol Mutagen

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“…Again, the results have been conflicting. The Rotterdam [18] and Pathologies Oculaires Liees al'Age [27] studies found an association between AMD risk and HDL-C. When separating by disease type, Klein et al [19] showed that higher serum HDL-C at baseline was associated with pure geographic atrophy or advanced non-neovascular AMD, while Hyman et al [20] revealed a positive association between HDL level and neovascular, but not non-neovascular AMD and dietary cholesterol level.…”

Section: Lipids and Amdmentioning

confidence: 99%

“…Part of this variability may have resulted from reporting different forms and stages of AMD with different lipid profiles. For example, several studies have not found an association between serum lipid profile and AMD risk [18,20,23]. Elevated HDL but not total cholesterol was associated with an increased risk of AMD in a study by Van Leeuwen et al [18] Non neovascular AMD was unrelated to cholesterol level in a study by Hyman et al [20] No difference in total cholesterol, triglycerides, phospholipids, HDL, LDL concentrations were observed between AMD patients and controls in the study by Abalain et al [23], and there was no significant difference in the concentration of the Lipoprotein(a) between the AMD and control groups in the work by Nowak et al [24].…”

Section: Lipids and Amdmentioning

confidence: 99%

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Role of Lipids in Retinal Vascular and Macular Disorders

2016

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Retinal diseases are significant by increasing problem in every part of the world. While excellent treatment has emerged for various retinal diseases, treatment for early disease is lacking due to an incomplete understanding of all molecular events. With aging, there is a striking accumulation of neutral lipids in Bruch's membrane. These neutral lipids leads to the creation of a lipid wall at the same locations where drusen and basal linear deposit, pathognomonic lesions of Age-related macular degeneration, subsequently form. High lipid levels are also known to cause endothelial dysfunction, an important factor in the pathogenesis of Diabetic Retinopathy. Various studies suggest that 20 % of Retinal Vascular Occlusion is connected to hyperlipidemia. Biochemical studies have implicated mutation in gene encoding ABCA4, a lipid transporter in pathogenesis of Stargardt disease. This article reviews how systemic and local production of lipids might contribute to the pathogenesis of above retinal disorders.

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“…For instance, retrospective studies have suggested that statins, which act on the rate-limiting enzyme of cholesterol synthesis (HMG-CoA reductase), decrease the risk of developing AD (6), and expression of specific allelic isoforms of apolipoprotein E, a cholesterol transport protein, is associated with an increased risk of developing AD (7). The relationship between statin use, apolipoprotein E isoform expression, and ARMD development or progression, although suggestive, is somewhat more speculative (8)(9)(10)(11). These findings provide the impetus for developing techniques to investigate cholesterol metabolism in the CNS.…”

mentioning

confidence: 99%

Enzyme blockade: a nonradioactive method to determine the absolute rate of cholesterol synthesis in the brain

Keller

Small

Fliesler

2004

Journal of Lipid Research

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The standard in vivo method to determine rates of brain cholesterol synthesis involves systemic injection of 3 H 2 O and measurement of incorporated radioactivity in sterols. Herein, we describe an alternative method ("enzyme blockade") that obviates the use of radioactivity. The method relies on the ability of AY9944, a potent and relatively selective inhibitor of cholesterol synthesis, to cause the time-dependent accumulation of 7-dehydrocholesterol (DHC), a cholesterol precursor detected with sensitivity and specificity by reverse-phase HPLC-coupled spectrophotometry at 282 nm. To validate the method, adult AY9944-treated and control mice were injected with [ 3 H]acetate. After 24 h, most of the radioactivity in brain sterols from treated mice accumulated in DHC, without significantly perturbing overall sterol pathway activity, compared with controls (where cholesterol was the dominant radiolabeled sterol, with no label found in DHC). When adult mice were treated continuously with AY9944, the time-dependent accumulation of DHC in brain was linear (after ‫ف‬ 8 h) for 3 days. The rate of brain cholesterol synthesis determined by this method ( ‫ف‬ 30 g/g/day) closely agrees with that determined by the radioactive method. We also determined the cholesterol synthesis rate in different regions of adult mouse brain, with frontal cortex having the highest rate and cerebellum having the lowest rate. There is growing interest in, and experimental documentation of, the relationship between central nervous system (CNS) cholesterol metabolism and neurodegeneration, particularly in age-related diseases such as Alzheimer's disease (AD) (1-3) and age-related macular degeneration (ARMD) (4, 5). For instance, retrospective studies have suggested that statins, which act on the rate-limiting enzyme of cholesterol synthesis (HMG-CoA reductase), decrease the risk of developing AD (6), and expression of specific allelic isoforms of apolipoprotein E, a cholesterol transport protein, is associated with an increased risk of developing AD (7). The relationship between statin use, apolipoprotein E isoform expression, and ARMD development or progression, although suggestive, is somewhat more speculative (8-11). These findings provide the impetus for developing techniques to investigate cholesterol metabolism in the CNS. In general, the rate of de novo cholesterol synthesis in the mammalian brain is relatively high in the fetus and newborn, where it is synthesized de novo, with little or no contribution from maternal sources (12, 13). Brain cholesterol synthesis decreases precipitously after weaning (14), as the rate of myelination dramatically declines [for review, see ref. (15)]. The fate of cholesterol in the adult CNS is uncertain, but all indications are that the turnover is relatively slow, with a half-life on the order of months (16). A portion of brain cholesterol is metabolized to 24 S -hydroxycholesterol, which then exits across the blood-brain barrier into the bloodstream (17). More than 50% of cholesterol release from...

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Cholesterol and age-related macular degeneration: is there a link?

Cited by 106 publications

References 6 publications

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Role of Lipids in Retinal Vascular and Macular Disorders

Enzyme blockade: a nonradioactive method to determine the absolute rate of cholesterol synthesis in the brain

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