Regulated expression of apolipoprotein E by human retinal pigment epithelial cells

Abstract

In early age-related macular degeneration (AMD), lipid-containing deposits (drusen) accumulate in Bruch's membrane underlying the retinal pigment epithelium (RPE).Recent studies indicate that apolipoprotein E (apoE) may play a role in lipid trafficking in AMD. Compared with the apoE3 allele, the apoE4 and apoE2 alleles are associated with decreased and increased risk for AMD, respectively; drusen contain high levels of apoE, and apoE null mice develop lipid deposits in Bruch's membrane similar to those observed in AMD. Primary cultures of human RPE cells expressing the apoE3 allele were grown on Transwell ® culture plates. Western blotting, ELISA assay, and mass spectrometry confirmed that apoE3 was secreted into the apical and basal chambers and that secretion was upregulated by thyroid hormone, 9-cis -retinoic acid, and 22( R )-hydroxycholesterol. In addition, basally secreted apoE associated with exogenously added HDL. These results indicate that apoE secretion can be regulated by specific hormones and that apoE associates with HDL. The findings are consistent with a role for apoE in lipid trafficking through Bruch's membrane and may be relevant to AMD. Age-related macular degeneration (AMD) is the leading cause of severe visual loss in the developed world (1, 2). In the early stages of the disease, before visual loss occurs from choroidal neovascularization, there is progressive accumulation of lipids in Bruch's membrane (3-6). Bruch's membrane lies at the critical juncture between the outer retina and its blood supply, the choriocapillaris. Lipid deposition causes reduced hydraulic conductivity and macromolecular permeability in Bruch's membrane and is thought to impair retinal metabolism (7-9). Interestingly, lipid accumulation in Bruch's membrane similar to that in AMD has been observed in apolipoprotein E (apoE) null mice (10, 11). Because of the additional association between apoE alleles and other age-related degenerations, such as Alzheimer's disease and atherosclerosis, there has been recent investigation into a potential role for apoE in AMD.Several studies of apoE polymorphism in AMD have been conducted (12)(13)(14). In contrast to Alzheimer's disease, the apoE4 allele has been associated with a reduced prevalence of AMD. The apoE2 allele is slightly increased in patients with AMD. Further supporting a role in AMD pathogenesis, apoE has been detected in drusen, the Bruch's membrane deposits that are the hallmark of AMD (13,15). Immunohistochemical studies of postmortem eyes have demonstrated apoE in the basal aspect of the retinal pigment epithelium (RPE) (15). Cultured RPE cells synthesize high levels of apoE mRNA, comparable to the levels found in brain (15).Although the role of apoE in AMD is not established, this apolipoprotein has several functions that may affect the course of this disease. ApoE has anti-angiogenic (16), anti-inflammatory (17), and anti-oxidative (18) effects. These are all considered atheroprotective attributes of apoE, but they may also be important in protecting a...

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

“…ApoE is expressed in photoreceptor outer-segments, the retinal ganglion layer, and both layers of Bruch's membrane. ApoE is also basally secreted by RPE cells [Anderson et al, 2001;Ishida et al, 2004]. It has been postulated that ApoE may facilitate lipid efflux from RPE cells and lipid transport across Bruch's membrane, thus reducing lipid deposit levels [Souied et al, 1998].…”

Degeneración macular asociada a la edad: asociación con el alelo épsilon4 del gen de la apolipoproteína E

“…However, it is difficult to establish the efficacy of these recommendations, which should be particularly emphasized for genetic risk subjects: family forms of AMD and some fenotype of APOE. AMD is a multifactorial pathology in which studies emphasise the importance of genetic factors (1,(7)(8)(9)(10)(11)(12)(13)(14). Recently, Hageman et al (7) in a study of F-factor gene (HF1/CFH) in a population of 900 patients with AMD and 400 controls, demonstrated the association between AMD and predisposition haplotypes (HF1 SNPs) and protection haplotypes.…”

“…It is synthesised mainly in the liver, with the brain being the second synthesis organ. In the retinal pigmentary epithelium there is a regulation in the expression of APOE (10). It presents 3 isoforms: E2, E3, E4, coded by three alleles ε2, ε3, and ε4, with a single locus in chromosome 19 (11).…”

Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

“…40 The role of ApoE in reverse cholesterol transport prompted the authors to suggest that this apolipoprotein may also facilitate the efflux of lipids from the RPE into the adjacent Bruch's membrane, and they proposed a possible pathway for RPE cell-secreted lipids to cross Bruch's membrane, where partially digested or undigested photoreceptor outer segments are secreted across the basal surface in association with ApoE. Subsequent binding with HDL at Bruch's membrane may then facilitate desorption of the lipid particles into circulation.…”

“…Subsequent binding with HDL at Bruch's membrane may then facilitate desorption of the lipid particles into circulation. 40 In the retina ApoE is synthesised in Mü ller cells and in the RPE, and the presence of ApoE has been demonstrated in drusen. 2,77 It has been suggested, therefore, that age or disease-related disruption of normal ApoE function may result in the accumulation of lipoproteins at the interface between the RPE and Bruch's membrane, consistent with observations that lipid deposits in drusen are largely composed of cholesteryl esters and unsaturated fatty acids.…”