Directional ABCA1-mediated cholesterol efflux and apoB-lipoprotein secretion in the retinal pigment epithelium

Abstract

Cholesterol-containing soft drusen and subretinal drusenoid deposits (SDDs) occur at the basolateral and apical side of the retinal pigment epithelium (RPE), respectively, in the chorioretina and are independent risk factors for late age-related macular degeneration (AMD). Cholesterol in these deposits could originate from the RPE as nascent HDL or apoB-lipoprotein. We characterized cholesterol efflux and apoB-lipoprotein secretion in RPE cells. Human RPE cells, ARPE-19, formed nascent HDL that was similar in physicochemical properties to nascent HDL formed by other cell types. In highly polarized primary human fetal RPE (phfRPE) monolayers grown in low-lipid conditions, cholesterol efflux to HDL was moderately directional to the apical side and much stronger than ABCA1-mediated efflux to apoA-I at both sides; ABCA1-mediated efflux was weak and equivalent between the two sides. Feeding phfRPE monolayers with oxidized or acetylated LDL increased intracellular levels of free and esterified cholesterol and substantially raised ABCA1-mediated cholesterol efflux at the apical side. phfRPE monolayers secreted apoB-lipoprotein preferentially to the apical side in low-lipid and oxidized LDL-feeding conditions. These findings together with evidence from human genetics and AMD pathology suggest that RPE-generated HDL may contribute lipid to SDDs. Cholesterol-containing soft drusen and subretinal drusenoid deposits (SDDs) occur at the basolateral and apical side of the retinal pigment epithelium (RPE), respectively, in the chorioretina and are independent risk factors for late age-related macular degeneration (AMD). Cholesterol in these deposits could originate from the RPE as nascent HDL or apoB-lipoprotein. We characterized cholesterol efflux and apoB-lipoprotein secretion in RPE cells. Human RPE cells, ARPE-19, formed nascent HDL that was similar in physicochemical properties to nascent HDL formed by other cell types. In highly polarized primary human fetal RPE (phfRPE) monolayers grown in low-lipid conditions, cholesterol efflux to HDL was moderately directional to the apical side and much stronger than ABCA1-mediated efflux to apoA-I at both sides; ABCA1-mediated efflux was weak and equivalent between the two sides. Feeding phfRPE monolayers with oxidized or acetylated LDL increased intracellular levels of free and esterified cholesterol and substantially raised ABCA1-mediated cholesterol efflux at the apical side. phfRPE monolayers secreted apoB-lipoprotein preferentially to the apical side in low-lipid and oxidized LDL-feeding conditions. These findings together with evidence from human genetics and AMD pathology suggest that RPE-generated HDL may contribute lipid to SDDs. Age-related macular degeneration (AMD) is a leading cause of vision loss in individuals 50 years of age and older (1.Bird A.C. Pathogenetic mechanisms in age-related macular degeneration.In Ryan's Retina. 2017; : 1285-1292Google Scholar). The pathogenesis of AMD involves abnormal deposition of lipid in the chorioretina (1.Bird A.C. Pathogenetic mechanisms in age-related macular degeneration.In Ryan's Retina. 2017; : 1285-1292Google Scholar, 2.Wenick A.S. Bressler S.B. Bressler N.M. Age-related macular degeneration: non-neovascular early AMD, intermediate AMD, and geographic atrophy.In Ryan's Retina. 2017; : 1293-1344Google Scholar, 3.de Jong P.T. Age-related macular degeneration.N. Engl. J. Med. 2006; 355: 1474-1485Crossref PubMed Scopus (720) Scholar). drusen and subretinal drusenoid deposits (SDDs) respectively, at the basolateral side of the retinal pigment epithelium in the and at the apical side of the RPE in the 2.Wenick A.S. Bressler S.B. Bressler N.M. Age-related macular degeneration: non-neovascular early AMD, intermediate AMD, and geographic atrophy.In Ryan's Retina. 2017; : 1293-1344Google Scholar, 3.de Jong P.T. Age-related macular degeneration.N. Engl. J. Med. 2006; 355: 1474-1485Crossref PubMed Scopus (720) Scholar, and pathology of Ryan's Retina. 2017; : Scholar, macular a of the and PubMed Scopus Scholar). In both of to of with PubMed Scopus Scholar, of soft drusen in age-related macular PubMed Scopus Scholar, deposits and drusen in with age-related evidence for lipid PubMed Scopus Scholar). drusen of and esterified and free cholesterol and for and apoA-I of cholesterol with age in human Scholar, J. and in human PubMed Scopus Scholar, and cholesterol in drusen and deposits of with age-related PubMed Scopus Scholar, and of the retinal pigment and the and with in human PubMed Scopus Scholar, of in human lipid PubMed Scopus Scholar). free cholesterol and for A.S. drusenoid by lipid PubMed Scopus Scholar, drusenoid deposits in human and PubMed Scopus Scholar). drusen in the of the are in the is by Bressler S.B. and the of geographic in age-related macular PubMed Scopus Scholar, AMD in age-related macular PubMed Scopus Scholar). drusen and occur together in the or and are independent risk factors for late AMD Bressler S.B. and the of geographic in age-related macular PubMed Scopus Scholar, AMD in age-related macular PubMed Scopus Scholar, The between subretinal drusenoid deposits in older in macular and age-related macular PubMed Scopus Scholar, of subretinal drusenoid deposits in older with and age-related macular by PubMed Scopus Scholar). that deposition of lipid in the chorioretina is in AMD The in J. PubMed Scopus Scholar, Cholesterol in the the is to PubMed Scopus Scholar). The in and of the with AMD in the of HDL cholesterol of age-related macular degeneration of and PubMed Scopus Scholar). The at are with levels The of and lipid PubMed Scopus Scholar, mechanisms in of age-related macular 2017; PubMed Scopus Scholar). a between levels and AMD risk mechanisms in of age-related macular 2017; PubMed Scopus Scholar). is with AMD risk in the between the two is the of of age-related macular degeneration with and lipid PubMed Scopus Scholar). between and is a of HDL properties in the of and a at and PubMed Scopus Scholar, in HDL cholesterol and risk of PubMed Scopus Scholar). are to at the basolateral and apical sides. from the the the of the and the basolateral side of the RPE and pathology of Ryan's Retina. 2017; : Scholar). between RPE the together with between and cell to the and Ryan's Retina. 2017; : Scholar, The Scholar). of the by of the secreted by the and and of the retinal PubMed Scopus Scholar, lipid is and 2006; Scholar). The the apical side of the The may lipid oxidized and age-related macular 2017; PubMed Scopus Scholar). RPE oxidized LDL J. RPE and oxidized LDL in in and in PubMed Scopus Scholar, and in primary retinal pigment PubMed Scopus Scholar, the the in human retinal pigment PubMed Scopus Scholar). Cholesterol with as to in the or the Cholesterol in the the is to PubMed Scopus Scholar, from the retinal epithelium lipid in other PubMed Scopus Scholar). Cholesterol with nascent HDL or with apoB-lipoprotein. The RPE for nascent HDL and and for apoB-lipoprotein secretion Cholesterol in the the is to PubMed Scopus Scholar). is in the basolateral and apical of the RPE lipid is and 2006; Scholar, of the of cholesterol in human PubMed Scopus Scholar). In cell that in both ABCA1-mediated cholesterol efflux to the basolateral side is stronger than to the apical side A.C. of cholesterol efflux from the apical and basolateral of PubMed Scholar, J. cholesterol and efflux in evidence for ABCA1-mediated J. PubMed Scopus Scholar, and of and cholesterol in and PubMed Scopus Scholar). is the in RPE The of secretion is a to the basolateral side The in J. PubMed Scopus Scholar, Cholesterol in the the is to PubMed Scopus Scholar). We cholesterol efflux in primary human fetal RPE (phfRPE) In phfRPE monolayers in a ABCA1-mediated cholesterol efflux at the basolateral side was equivalent to ABCA1-mediated cholesterol efflux at the apical secretion was stronger at the apical side. In phfRPE monolayers with or acetylated LDL to intracellular cholesterol ABCA1-mediated cholesterol efflux at the apical side was stronger than at the basolateral secretion stronger at the apical than at the basolateral side. 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We a polarized phfRPE to in the RPE a phfRPE monolayers of in with a the of between RPE of the monolayers was The monolayers secreted to the basolateral and apical apoA-I could in side with or a The phfRPE monolayers cell and for in of the phfRPE and deposits at the basolateral side of the between phfRPE and the could in the of the with that deposits and in The apical of the phfRPE for deposits the apical of phfRPE phfRPE cell and deposition of in RPE similar to for the of RPE by other pigment deposition of drusen in a primary cell 2017; PubMed Scopus Scholar, J. that drusen and with age-related macular PubMed Scopus Scholar). phfRPE is a of the The of phfRPE to in a and of these monolayers of human fetal retinal pigment epithelium and of 2006; PubMed Scopus Scholar). phfRPE monolayers that in for for of and and with was in phfRPE monolayers with of in phfRPE monolayers was and independent of These findings that in the RPE is by as in other cell and efflux of cholesterol to a of PubMed Scopus Scholar, lipid and HDL to the for the of HDL PubMed Scopus Scholar). In the RPE is to and HDL from the at the basolateral side and to and HDL from the at the apical side and pathology of Ryan's Retina. 2017; : Scholar, lipid is and 2006; Scholar). in the cholesterol efflux could occur at both We to cholesterol efflux to apoA-I and HDL at the apical and basolateral of phfRPE monolayers the conditions. phfRPE monolayers with with and to cholesterol apoA-I or for The of with the of the was to the basolateral and to the apical of the Cholesterol efflux to cholesterol was at the basolateral than at the apical side of apoA-I a in cholesterol efflux at the basolateral side and a efflux at the apical side The efflux to was from the efflux to with apoA-I the efflux to apoA-I and to at the basolateral side than at the apical side of HDL increased cholesterol efflux at both The efflux to was from the efflux to with HDL the efflux to HDL at the apical side than at the basolateral side efflux to apoA-I at the basolateral side and efflux to apoA-I at the apical side These in the low-lipid conditions, efflux by the to apoA-I from the RPE is weak and efflux by and to HDL is and moderately with a to the apical side. the of to or the intracellular cholesterol levels in the phfRPE monolayers in 50 or 50 for was by and was cells. of ABCA1-mediated cholesterol efflux in by that LDL was oxidized substantially efflux from oxidized PubMed Scopus Scholar). phfRPE and with a lipid the the and for the lipid for free and esterified cholesterol was as of cholesterol of cell with and increased intracellular cholesterol by similar and phfRPE grown in esterified cholesterol with or esterified cholesterol and respectively, of the cell esterified cholesterol and of the cholesterol with or These that and are at intracellular cholesterol levels in the We levels of intracellular lipid and oxidized lipid ABCA1-mediated cholesterol efflux in the phfRPE phfRPE monolayers in for to cell to a of lipid in the with to 50 or 50 for and with for phfRPE monolayers in to or with a of apoA-I for monolayers or to apoA-I for and apical and with to apoB-lipoprotein for the of from human by with PubMed Scholar). was lipid with or could apoB-lipoprotein secretion and ABCA1-mediated cholesterol efflux Cholesterol efflux to cholesterol from phfRPE monolayers in was at the basolateral and apical sides; of apoA-I increased cholesterol efflux at both the basolateral cholesterol efflux to apoA-I from and monolayers was the and moderately respectively, in with efflux to apoA-I from monolayers at the apical cholesterol efflux to apoA-I was much stronger from and monolayers than from and cholesterol efflux to apoA-I from monolayers was much stronger than from monolayers The efflux to apoA-I was from of the efflux to with apoA-I at both sides; the cholesterol efflux to apoA-I from phfRPE monolayers between the basolateral and apical Cholesterol efflux to apoA-I from and phfRPE monolayers was and respectively, stronger at the apical side than at the basolateral side These suggest that lipid of phfRPE with or cholesterol efflux to apoA-I preferentially at the apical side and that phfRPE are at of cholesterol with than with in the lipid in the apical than in the basolateral of the phfRPE was to or that apoB-lipoprotein was preferentially secreted to the apical side. phfRPE monolayers in or 50 for and to in for in the of cholesterol in of efflux the was with to and in the the in and was to apoB-lipoprotein. The efflux was and by The and phfRPE monolayers to and secreted respectively, of in apoB-lipoprotein to the apical side than to the basolateral side the of in the apical of and phfRPE could in the basolateral from the monolayers apoB-lipoprotein secretion phfRPE monolayers in to for from both and with could in the from both sides; the in the apical was much stronger than in the basolateral of phfRPE monolayers in for and levels in the a could in the basolateral the apical These suggest that the phfRPE apoB-lipoprotein preferentially to the apical side and to levels of In cholesterol in the RPE RPE cell ARPE-19, and phfRPE that and the as nascent and the in and two of the as nascent HDL by other cell of these by was to ABCA1-mediated cholesterol efflux nascent and cell lipid and J. PubMed Scopus Scholar, lipid and HDL to the for the of HDL PubMed Scopus Scholar, nascent and 2017; PubMed Scopus Scholar). by is nascent In the of phfRPE monolayers and to HDL as the of cell cholesterol ABCA1-mediated cholesterol efflux to apoA-I was Cholesterol efflux to HDL was moderately polarized to the apical cholesterol efflux to apoA-I was equivalent at the two sides. intracellular cholesterol levels by phfRPE with or cholesterol efflux to apoA-I by than two at the apical the at the basolateral side. apoB-lipoprotein secretion preferentially to the apical side in low-lipid and phfRPE with These a of cholesterol by the RPE in to lipid Cholesterol efflux in the RPE to the in In is the of cholesterol ABCA1-mediated cholesterol efflux to apoA-I to the cell cholesterol The of in the of cholesterol from PubMed Scopus Scholar). to apoA-I a of cholesterol in with cholesterol by with The of in the of cholesterol from PubMed Scopus Scholar). phfRPE the and ABCA1-mediated of cholesterol efflux in ABCA1-mediated efflux in these at the apical side. Feeding with to or ABCA1-mediated cholesterol efflux from oxidized PubMed Scopus Scholar, of oxidized PubMed Scopus Scholar). We of ABCA1-mediated efflux to apoA-I in as a of the of RPE at of than the the in human retinal pigment PubMed Scopus Scholar, efflux from oxidized PubMed Scopus Scholar, of oxidized PubMed Scopus Scholar, J. of LDL and HDL retinal pigment a in PubMed Scopus Scholar, J. a by retinal PubMed Scopus Scholar). and phfRPE the of phfRPE in cholesterol efflux to was than in the phfRPE to is the of the RPE to in the a the basolateral and apical of in and cholesterol and to the free of and in the PubMed Scopus Scholar). efflux of cholesterol by the ABCA1-mediated and other to the basolateral or apical side in of epithelium A.C. of cholesterol efflux from the apical and basolateral of PubMed Scholar, J. cholesterol and efflux in evidence for ABCA1-mediated J. PubMed Scopus Scholar, and of and cholesterol in and PubMed Scopus Scholar). In the RPE secretion by RPE secretion by the retinal pigment in retinal and the of age-related macular Med. PubMed Scopus Scholar). We directional and ABCA1-mediated efflux in the RPE The of cholesterol efflux to of the efflux in lipid and cholesterol or of the two to the free of and in the PubMed Scopus Scholar). is of these factors are at in the of and in the RPE and cholesterol efflux from RPE Cholesterol in the the is to PubMed Scopus Scholar, lipid is and 2006; Scholar, of the of cholesterol in human PubMed Scopus Scholar, of cholesterol and in the and retinal pigment J. PubMed Scopus Scholar, S.B. of the cholesterol efflux and in in and by the PubMed Scopus Scholar, lipid efflux from retinal pigment in J. 2006; PubMed Scopus Scholar, J. efflux of cholesterol by human RPE 2017; PubMed Scopus Scholar). to the basolateral and apical and ABCA1-mediated efflux at both of phfRPE basolateral and apical efflux J. efflux of cholesterol by human RPE 2017; PubMed Scopus Scholar). S.B. of the cholesterol efflux and in in and by the PubMed Scopus a of to the apical in RPE the efflux to the apical side by the ABCA1-mediated in to and of the apoB-lipoprotein. In and of the apoB-lipoprotein secretion intracellular levels of J. PubMed Scopus Scholar, J. of in and secretion and cell 2017; PubMed Scopus Scholar, J. of in the lipid PubMed Scopus Scholar). that apoB-lipoprotein secreted by the RPE to the LDL of the of cholesterol in human PubMed Scopus Scholar, The and of cholesterol in the PubMed Scopus Scholar). of the in the human and is to vision and of the retinal pigment and the and with in human PubMed Scopus Scholar, in in macular and other PubMed Scopus Scholar). is in the are by and are by RPE in in macular and other PubMed Scopus Scholar). that from the and in the RPE and is from the RPE to in in macular and other PubMed Scopus Scholar). RPE in the and are to in by the ABCA1-mediated and of the retinal pigment and the and with in human PubMed Scopus Scholar). secretion to the side is with the that apoB-lipoprotein is the of in the The RPE is to from the at the basolateral side and to from the at the apical side lipid is and 2006; Scholar, J. RPE and oxidized LDL in in and in PubMed Scopus Scholar). to in the LDL by the free and of lipid as in the of the RPE to levels that in RPE cell in as a of and is in levels in PubMed Scopus Scholar, and in the a free PubMed Scopus Scholar). The RPE of a for and both the basolateral side and the apical side and LDL J. RPE and oxidized LDL in in and in PubMed Scopus Scholar, in the of by retinal pigment PubMed Scholar, J. in the of and PubMed Scopus Scholar). RPE and for cholesterol to in apoB-lipoprotein and and to Cholesterol in the the is to PubMed Scopus Scholar, of the of cholesterol in human PubMed Scopus Scholar, of the of cholesterol and in of age-related macular 2017; PubMed Scopus Scholar). is to cholesterol in the in apoB-lipoprotein and may contribute cholesterol to soft drusen and respectively, in the at the basolateral side and in the at the apical side of the are factors in AMD A.S. Bressler S.B. Bressler N.M. Age-related macular degeneration: non-neovascular early AMD, intermediate AMD, and geographic atrophy.In Ryan's Retina. 2017; : 1293-1344Google Scholar). The RPE could a of lipid in or both ABCA1-mediated cholesterol nascent HDL to the apical side in phfRPE monolayers that RPE-generated HDL conditions, contribute lipid to SDDs. is in the of cholesterol at the apical cholesterol to the basolateral side and is by the ABCA1-mediated the lipid to soft at the basolateral side of the RPE from the lipid at the apical side. could of lipid at both of cholesterol at both or of cholesterol the basolateral the apical or The a of phfRPE monolayers as a for lipid in the chorioretina and the of lipid to the RPE could in is to lipid at the basolateral and apical side that deposition of the of soft drusen and and free cholesterol for soft drusen and and free cholesterol for SDDs. Human and evidence for in at the that levels and in the are for AMD The of and lipid PubMed Scopus Scholar, mechanisms in of age-related macular 2017; PubMed Scopus Scholar). is RPE HDL and may cholesterol to Cholesterol in the the is to PubMed Scopus Scholar). HDL in the and and soft drusen and at the are with LDL cholesterol and with AMD of age-related macular degeneration of and PubMed Scopus Scholar, A.S. for 2017; PubMed Scopus Scholar). apoB-lipoprotein secreted by as a soft drusen and are of Cholesterol in the the is to PubMed Scopus Scholar, J. of in and secretion and cell 2017; PubMed Scopus Scholar, J. of in the lipid PubMed Scopus Scholar). is in soft drusen as as in is in a of soft drusen and pathology of Ryan's Retina. 2017; : Scholar, A.S. drusenoid by lipid PubMed Scopus Scholar). AMD may a in a The cell ARPE-19, was to nascent HDL for by is to of phfRPE for of nascent HDL in of and HDL the at the basolateral and apical of phfRPE the RPE is to of and cholesterol at the two in Human suggest that levels of are in AMD of age-related macular degeneration of and PubMed Scopus Scholar, The of and lipid PubMed Scopus phfRPE monolayers with to and cholesterol was cholesterol in phfRPE monolayers at levels to of and We and that and and respectively, and other cholesterol efflux and efflux of cholesterol to a of PubMed Scopus Scholar, lipid and HDL to the for the of HDL PubMed Scopus Scholar, of and ABCA1-mediated cholesterol by the and PubMed Scopus Scholar). In cholesterol in the RPE is similar to cholesterol in from that the RPE nascent HDL that are similar in physicochemical properties to nascent HDL formed by and other cell types. of in low-lipid conditions, phfRPE monolayers cholesterol by and to as with a to the apical ABCA1-mediated efflux of apoA-I is weak and equivalent between the two sides. Feeding phfRPE with or and esterified intracellular cholesterol levels and ABCA1-mediated efflux at the apical ABCA1-mediated efflux at the basolateral side apoB-lipoprotein secretion is preferentially to the apical side in low-lipid and These suggest that LDL and nascent HDL by the ABCA1-mediated may contribute lipid to the of are the apical side of the and evidence of apoB-lipoprotein in the of soft are at the basolateral side of the The for for for with and for with cell for the and for a The to and from of for in phfRPE acetylated LDL age-related macular degeneration HDL cholesterol oxidized LDL primary human fetal retinal pigment epithelium retinal pigment epithelium subretinal drusenoid