Selective retinal pigment epithelial cell lipid metabolism and remodeling conserves photoreceptor docosahexaenoic acid following phagocytosis

Turco, Elena; Parkins, Nilda; Ershov, A. V.; Bazán, Nicolás G.

doi:10.1002/(sici)1097-4547(19990815)57:4<479::aid-jnr7>3.0.co;2-u

Cited by 43 publications

(23 citation statements)

References 36 publications

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“…Several lines of evidence suggest that OS phagocytosis is tightly coupled to RPE lipid and cholesterol metabolism: (i) Phagocytosis triggers expression of the AP-2 transcription factor (25), which regulates acid lipase expression (26); (ii) OS phagocytosis induces PPAR␥ (25), which increases transcription of cholesterol transporters (21); and (iii) selective metabolism of OS lipids by the RPE leads to the conservation and recycling of docosahexaenoic acid (27). In addition, RPE cells express several receptors and cholesterol transporters (28) that participate in lipoprotein uptake and cholesterol efflux.…”

Section: Discussionmentioning

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.

144

145

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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%

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

Lakkaraju

Finnemann

Rodríguez-Boulan

2007

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

144

145

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“…It has been hypothesized that cholesterol can be obtained from systemic sources and that it can be recycled within the retina [51]. This is consistent with the recycling of a major fatty acid, docosahexaenoic acid (DHA) in the retina [52][53][54]. In this recycling process lipids from phagocytosed apical disks are returned from the pigment epithelium to the rod cell and then reused in the synthesis of new disks.…”

Section: Cholesterol Biosynthesismentioning

confidence: 78%

The role of cholesterol in rod outer segment membranes

Albert

Boesze‐Battaglia

2005

Progress in Lipid Research

111

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The photoreceptor rod outer segment (ROS) provides a unique system in which to investigate the role of cholesterol, an essential membrane constituent of most animal cells. The ROS is responsible for the initial events of vision at low light levels. It consists of a stack of disk membranes surrounded by the plasma membrane. Light capture occurs in the outer segment disk membranes that contain the photopigment, rhodopsin. These membranes originate from evaginations of the plasma membrane at the base of the outer segment. The new disks separate from the plasma membrane and progressively move up the length of the ROS over the course of several days. Thus the role of cholesterol can be evlauated in two distinct membranes. Furthermore, because the disk membranes vary in age it can also be investigated in a membrane as a function of the membrane age. The plasma membrane is enriched in cholesterol and in saturated fatty acids species relative to the disk membrane. The newly formed disk membranes have 6-fold more cholesterol than disks at the apical tip of the ROS. The partitioning of cholesterol out of disk membranes as they age and are apically displaced is consistent with the high PE content of disk membranes relative to the plasma membrane. The cholesterol composition of membranes has profound consequences on the major protein, rhodopsin. Biophysical studies in both model membranes and in native membranes have demonstrated that cholesterol can modulate the activity of rhodopsin by altering the membrane hydrocarbon environment. These studies suggest that mature disk membranes initiate the visual signal cascade more effectively than the newly synthesized, high cholesterol basal disks. Although rhodopsin is also the major protein of the plasma membrane, the high membrane cholesterol content inhibits rhodopsin participation in the visual transduction cascade. In addition to its effect on the hydrocarbon region, cholesterol may interact directly with rhodopsin. While high cholesterol inhibits rhodopsin activation, it also stabilizes the protein to denaturation. Therefore the disk membrane must perform a balancing act providing sufficient cholestrol to confer stability but without making the membrane too restrictive to receptor activation. Within a given disk membrane, it is likely that cholesterol exhibits an asymmetric distribution between the inner and outer bilayer leaflets. Furthremore, there is some evidence of cholesterol microdomains in the disk membranes. The availability of the disk protein, rom-1 may be sensitive to membrane cholesterol. The effects exerted by cholesterol on rhodopsin function have far-reaching implications for the study of G-protein coupled receptors as a whole. These studies show that the function of a membrane receptor can be modulated by modification of HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript the lipid bilayer, particularly cholesterol. This provides a powerful means of fine-tuning the activity of a membrane protein without resorting ...

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“…However, lipoprotein assembly and secretion as a mechanism to release FFA from OS phospholipids as TG is an attractive hypothesis. Limited data on mammalian RPE support this notion, as intracellular TG in rat RPE cells increase for 4 h and decline over 24 h after OS phagocytosis in vivo (67) and in vitro (68). That OS phagocytosis, a uniquely eyespecific activity, should contribute lipids to ARM-associated lesions is a widely held expectation (69), but an output mechanism from RPE has never been specified.…”

Section: Discussionmentioning

confidence: 99%

Retina expresses microsomal triglyceride transfer protein: implications for age-related maculopathy

Presley

Zhang

et al. 2005

Journal of Lipid Research

105

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The principal extracellular lesions of age-related maculopathy (ARM), the leading cause of vision loss in the elderly, involve Bruch's membrane (BrM), a thin vascular intima between the retinal pigment epithelium (RPE) and its blood supply. With age, 80-100 nm solid particles containing esterified cholesterol (EC) accumulate in normal BrM, and apolipoprotein B (apoB) immunoreactivity is detectable in BrM-and ARM-associated lesions. Yet little evidence indicates that increased plasma cholesterol is a risk factor for ARM. To determine if RPE is capable of assembling its own apoB-containing lipoprotein, we examined RPE for the expression of microsomal triglyceride transfer protein (MTP), which is required for this process. Embryologically part of the central nervous system, the retina ( Fig. 1A ) converts light energy to electrochemical signals for transmission to the brain. The photoreceptors are supported by the retinal pigment epithelium (RPE), a monolayer with diverse functions including daily phagocytosis of the distal tips of photoreceptor outer segments (OS), and the choroid, a vascular bed with the body's highest blood flow. The choriocapillaris is a dense capillary plexus in the innermost choroid, and Bruch's membrane (BrM) is a thin vascular intima between the RPE and the choriocapillaris (Fig. 1B, arrowheads). In human retina, the macula subserves high-acuity vision and is vulnerable to age-related maculopathy (ARM), the major cause of vision loss among the elderly of industrialized societies. The most prominent histopathologic and clinical signs of ARM are extracellular lesions [drusen (Fig. 1E, F) and basal linear deposits (not shown)] in the RPE/BrM complex that ultimately impact vision by the photoreceptors (1, 2). Choroidal neovascularization, an invasion of choriocapillaries across BrM and lateral spread within the plane of drusen and basal linear deposit (see 3), is the principal sight-threatening complication of ARM's obscure underlying degeneration.Recent findings highlight a role for lipids and lipoproteins in this degeneration. These include a protective effect of the apolipoprotein E4 (apoE4) genotype in populations and the presence of apoB and apoE and histochemically identified lipids in aging-and ARM-associated drusen and deposits in human tissues (4-8) (Fig. 1E, F). The best established risk factor for early ARM is advanced age (9). A Abbreviations: ABL, abetalipoproteinemia; apoB, apolipoprotein B; apoBEC-1, apolipoprotein B-editing complex-1; ARM, age-related maculopathy; BrM, Bruch's membrane; EC, esterified cholesterol; ESI/MS, electrospray ionization mass spectrometry; INL, inner nuclear layer; MCT3, monocarboxylate transporter 3; MTP, microsomal triglyceride transfer protein; OS, outer segments of photoreceptors; RGC, retinal ganglion cell; RPE, retinal pigment epithelium; TC, total cholesterol; TG, triglyceride; UC, unesterified cholesterol.

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Selective retinal pigment epithelial cell lipid metabolism and remodeling conserves photoreceptor docosahexaenoic acid following phagocytosis

Cited by 43 publications

References 36 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

The role of cholesterol in rod outer segment membranes

Retina expresses microsomal triglyceride transfer protein: implications for age-related maculopathy

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