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C. Li, G. Malek, X. Zhang, C.A. Curcio; Genes for Apolipoprotein B (APO B) and Microsomal Triglyceride Transfer Protein (MTP) Are Expressed in Human Retina and Retinal Pigment Epithelium (RPE) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2287.
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Purpose: To evaluate the potential for intraocular biosynthesis of apo B containing lipoproteins. MTP is required for efficient assembly of hepatic very low-density lipoprotein (VLDL), intestinal chylomicrons, and cardiac LDL. MTP is a soluble microsomal heterodimer consisting of a multifunctional 58KD protein disulfide isomerase (PDI) and a unique large 97KD protein that transfers neutral lipid to nascent apo B. Methods: Human donor eyes <5 hr post-mortem, with normal maculas, were used. Retina, RPE, and cultured ARPE-19 cells were subjected to RT-PCR and Western blot for MTP, apo B, and PDI, using human hepatoma HepG2 cells as positive controls. The apo B RT-PCR product was sequenced. For immunohistochemistry, cryo-sections through retina and choroid of paraformaldehyde-preserved eyes were stained with antibodies to apo B, MTP and Brn3a, a ganglion cell (GC) marker. Results: Apo B, MTP, and PDI were expressed in retina, RPE, and ARPE-19 cells, as demonstrated by RT-PCR, Western blot and immunohistochemistry. Sequencing the apo B mRNA editing-site fragment indicated that RPE expresses full-length apo B-100, like liver, not the apo B-48 found in intestine. Apo B and MTP co-localized in GC. Apo B but not MTP was found in Bruch’s membrane (BrM). Conclusions: 1) Abetalipoproteinemia (ABL) is an autosomal recessive disorder characterized by the absence of apo B caused by null mutations of MTP gene. Hypobetalipoproteinemia (HBL) is a co-dominant disorder characterized by decreased apo B caused by frame-shift or stop-codon mutations of apo B gene. Both disorders include fat malabsorption, ataxic neuropathy, and retinitis pigmentosa. Visual dysfunction in ABL and HBL is attributed to vitamin A and E insufficiency due to lack of chylomicrons. MTP/ apo B expression in retina and RPE raises the possibility of a direct effect in addition to vitamin insufficiency. 2) A neuronal MTP/ apo B pathway is novel. Its function in GC is unknown. 3) We previously showed esterified cholesterol, apo B, and 80-100 nm diameter particles in BrM. All cells expressing MTP assemble large lipoproteins containing triglyceride and esterified cholesterol as part of forward fuel (liver and intestine) or reverse triglyceride transport systems (heart). A large lipoprotein is a plausible mechanism for disposal of outer segment lipids by RPE. 4) Drusen and basal deposits in aging and age-related maculopathy contain cholesterol and apo B (Malek et al., Am J Pathol, 2003). An abnormality of a constitutive apo B-containing lipoprotein pathway is a plausible mechanism for producing these lesions.
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