Regulation of the cholesterol efflux transporters ABCA1 and ABCG1 in retina in hemochromatosis and by the endogenous siderophore 2,5-dihydroxybenzoic acid.
Hypercholesterolemia and polymorphisms in the cholesterol exporter ABCA1 are linked to age-related macular degeneration (AMD). Excessive iron in retina also has a link to AMD pathogenesis. Whether these findings mean a biological/molecular connection between iron and cholesterol is not known. Here we examined the relationship between retinal iron and cholesterol using a mouse model (Hfe(-/-)) of hemochromatosis, a genetic disorder of iron overload. We compared the expression of the cholesterol efflux transporters ABCA1 and ABCG1 and cholesterol content in wild type and Hfe(-/-) mouse retinas. We also investigated the expression of Bdh2, the rate-limiting enzyme in the synthesis of the endogenous siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA) in wild type and Hfe(-/-) mouse retinas, and the influence of this siderophore on ABCA1/ABCG1 expression in retinal pigment epithelium. We found that ABCA1 and ABCG1 were expressed in all retinal cell types, and that their expression was decreased in Hfe(-/-) retina. This was accompanied with an increase in retinal cholesterol content. Bdh2 was also expressed in all retinal cell types, and its expression was decreased in hemochromatosis. In ARPE-19 cells, 2,5-DHBA increased ABCA1/ABCG1 expression and decreased cholesterol content. This was not due to depletion of free iron because 2,5-DHBA (a siderophore) and deferiprone (an iron chelator) had opposite effects on transferrin receptor expression and ferritin levels. We conclude that iron is a regulator of cholesterol homeostasis in retina and that removal of cholesterol from retinal cells is impaired in hemochromatosis. Since excessive cholesterol is pro-inflammatory, hemochromatosis might promote retinal inflammation via cholesterol in AMD.
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
Sudha
S
Ananth
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
Jaya P
JP
Gnana-Prakasam
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
Yangzom D
YD
Bhutia
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
Rajalakshmi
R
Veeranan-Karmegam
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
Pamela M
PM
Martin
Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA 30912, USA.
Sylvia B
SB
Smith
Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: vganapat@gru.edu.
Vadivel
V
Ganapathy
D064286:ATP Binding Cassette Transporter 1 / Q000502:physiology*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D019175:DNA Methylation; D005841:Gentisates / Q000378:metabolism*; D006432:Hemochromatosis / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D008074:Lipoproteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D012160:Retina / Q000378:metabolism*; D017262:Siderophores / Q000502:physiology*
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D005841:Gentisates; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008074:Lipoproteins; D008565:Membrane Proteins; D017262:Siderophores; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C499535:Hfe protein, mouse; C010925:2,5-dihydroxybenzoic acid
Cholesterol transport; Hemochromatosis; Mammalian siderophore; Retinal pigment epithelial cells; β-Hydroxybutyrate dehydrogenase-2