Lipoprotein-like Particles and Cholesteryl Esters in Human Bruch’s Membrane: Initial Characterization

Li, Chuanming; Chung, Byung Hong; Presley, Jennifer B.; Malek, Goldis; Zhang, Xueming; Dashti, Nassrin; Li, Ling; Chen, Jianguo; Bradley, Kelley M.; Kruth, Howard S.; Curcio, Christine A.

doi:10.1167/iovs.05-0034

Cited by 131 publications

(151 citation statements)

References 53 publications

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“…The presence of cholesterol and CE deposits in the Bruch's membrane of AMD eyes (9,10) and the correlation of genetic variations in cholesterol transporters with AMD susceptibility (12,13) point to an age-related alteration in cholesterol homeostasis in the RPE that may contribute to AMD progression. In this context, it is noteworthy that cholesterol and CE deposits in the Bruch's membrane are thought to originate from the RPE, including incompletely processed OS and additional sources such as the RPE itself (9).…”

Section: Discussionmentioning

confidence: 99%

“…Progressive lipid and cholesterol accumulation in the Bruch's membrane beneath the RPE has been identified as a contributing factor to age-related macular degeneration (AMD) (5). Apolipoproteins, cholesterol and cholesteryl esters (CE) are abundant in both drusen (lipid-protein aggregates in the Bruch's membrane) and other subRPE deposits in AMD eyes (9)(10)(11), suggesting compromised cholesterol homeostasis in the RPE. Moreover, cardiovascular disease and allelic variants in apolipoprotein E and ATP-binding cassette protein A1 (ABCA1) have been linked to AMD susceptibility in humans (12,13).…”

Section: Proteins Involved In Cholesterol Traffickingmentioning

confidence: 99%

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The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

Lakkaraju

Finnemann

Rodríguez-Boulan

2007

Proc. Natl. Acad. Sci. U.S.A.

141

143

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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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Section: Discussionmentioning

confidence: 99%

Section: Proteins Involved In Cholesterol Traffickingmentioning

confidence: 99%

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

Lakkaraju

Finnemann

Rodríguez-Boulan

2007

Proc. Natl. Acad. Sci. U.S.A.

141

143

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“…Classically, these BM defects have been described as fragmentation or fracturing in association with calcification (81)(82)(83)(84)(85). Additional age-related changes in BM are typified by: 1) progressive thickening of the two collagenous layers; 2) modification and degeneration of collagen and elastin; 3) increased levels of advanced glycation end products, noncollagenous proteins and lipids; and 4) accumulation of several types of sub-RPE deposits (86)(87)(88)(89)(90)(91)(92)(93)(94)(95). It has also been suggested that the age-related abnormalities in BM eventually lead to photoreceptor degeneration as a result of increased hydrophobicity, reduced permeability, and impaired nutrient exchange between the choroid and the RPE.…”

Section: Morphological Correlates Of Early Amdmentioning

confidence: 99%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene-which encodes the major inhibitor of the complement alternative pathway-is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

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“…One possible mechanism of accumulation could be the embedding of the LLPs in the fibrils either due to higher filament density in that region (Starita et al, 1997) or increased cross-linking of fibrils (Karwatowski et al, 1995;Handa et al, 1999). The recent discovery of potential apolipoprotein B-100 (ApoB-100) on the LLPs (Li et al, 2005a(Li et al, , 2006 suggests that this attachment might be similar to the mechanism causing low density lipoprotein (LDL) accumulation in the vascular intima. It has been postulated that LDL accumulation in vascular intima is initiated by the ApoB-100 interacting with the sulphate groups of the proteoglycans and further promoted by the oxidative modification of LDL (Williams and Tabas, 1995;Change et al, 2001;Wang et al, 2001;Skalen et al, 2002;Stocker and Keaney, 2004;Vijayagopal and Menon, 2005).…”

Section: Possible Mechanism Of Llp Accumulationmentioning

confidence: 99%

Age-related changes in human macular Bruch's membrane as seen by quick-freeze/deep-etch

Huang

Presley

Chimento

et al. 2007

Experimental Eye Research

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Lipid-containing inclusions have been observed in human Bruch's membrane (BrM) and are postulated to be associated with age-related maculopathy (ARM), a major cause of legal blindness in developed countries. The dehydration associated with specimen preparation for thin-section transmission electron microscopy causes loss of these inclusions. Better preservation of the ultrastructure of the inclusions and tissue is achieved by using a quick-freeze/deep-etch preparation. We use this technique to examine normal human macular BrM in order to characterize the deposition of the lipid-rich inclusions and their age-related accumulation within different layers of the tissue. We find that various inclusions mentioned in other studies can be formed by combinations of three basic structures: lipoprotein-like particles (LLPs), small granules (SGs) and membrane-like structures. These inclusions are associated with collagen and elastic fibrils by fine filaments. In younger eyes, these inclusions are found mostly in the elastic (EL) and outer collageneous layer (OCL) and occupy a small fraction of the interfibrillar spacing. As age increases, LLPs and SGs gradually fill the interfibrillar spacing of the EL and inner collageneous layer (ICL) of the tissue, and later form a new sublayer, the lipid wall, within the boundary region between the basal lamina of retinal pigment epithelium (RPE) and ICL. Because the formation of the lipid wall only occurs after these inclusions fill the ICL, and it seems unlikely that the LLPs can pass through the packed layer, this result suggests a possible RPE origin of the LLPs that make up the lipid wall.

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Lipoprotein-like Particles and Cholesteryl Esters in Human Bruch’s Membrane: Initial Characterization

Cited by 131 publications

References 53 publications

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Age-related changes in human macular Bruch's membrane as seen by quick-freeze/deep-etch

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