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

Abstract

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.

Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration

“…Of major importance to the apoB system is the presence of both mRNA and protein for the large subunit of microsomal triglyceride transfer protein (MTP) within native human RPE. The latter was localized with apoB itself to punctate intracellular bodies, presumably endoplasmic reticulum, within both the RPE and, surprisingly, ganglion cells of the neurosensory retina ( 108 ). Mouse RPE expresses both MTP isoforms ( 110 ).…”

“…mRNA transcripts for both apoE and apoB have been confi rmed in human RPE and RPE/choroid preparations ( 57,107,108 ), with apoE expression levels third behind brain and liver ( 62 ). RPE contains mRNA transcripts for apos A-I, C-I, and C-II, but not C-III ( 57,64,109 ).…”

“…RPE contains mRNA transcripts for apos A-I, C-I, and C-II, but not C-III ( 57,64,109 ). Full-length apoB protein was localized to native RPE using a specifi c monoclonal antibody ( 57,108 ). Of signifi cance to the apoB system, apoBEC-1 mRNA is not detectable in human RPE ( 108 ).…”

“…Full-length apoB protein was localized to native RPE using a specifi c monoclonal antibody ( 57,108 ). Of signifi cance to the apoB system, apoBEC-1 mRNA is not detectable in human RPE ( 108 ). However, it is present in rat RPE and the rat-derived RPE-J cell line (L. Wang and C. A. Curcio, unpublished observations), along with an apoB-48-like protein immunoprecipitable by anti-rat apoB ( 96 ), suggesting that rat RPE expresses both apoB-100 and apoB-48 as does liver in this species.…”

Lipoproteins and Apolipoproteins of the Ageing Eye

“…[101;102] This evidence is further strengthened by the finding of microsomal triglyceride transfer protein within native human RPE, indicating that the RPE is capable of secreting lipoprotein particles. [102] The pattern of lipid deposition in BrM with age, in which debris appears firstly in the elastic layer and then fills in towards the RPE, is also consistent with this lipid being primarily of RPE origin. [103] The hydrophobic nature of the age-related thickening of BrM has been implicated in the aetiopathogenesis of AMD.…”