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Sudha Ananth, Brooke Baldowski, Pamela Martin, Sylvia Smith, Vadivel Ganapathy; Regulation of the cholesterol efflux transporters ABCA1/ABCG1 in retina in hemochromatosis and by the endogenous iron chelator 2,5-dihydroxybenzoic acid. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1378.
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© ARVO (1962-2015); The Authors (2016-present)
Iron is obligatory for retinal function, but excessive iron is detrimental. Retinal iron is increased in hemochromatosis. Recently an endogenous iron chelator, 2,5-dihydroxybenzoic acid, has been identified, whose synthesis is mediated by Bdh2. Here we investigated the expression of Bdh2 in wild type and hemochromatosis mouse retinas, and the influence of the endogenous iron chelator on the expression of the cholesterol efflux transporters ABCA1 and ABCG1.
Bdh2 expression in mouse retina was examined by RT-PCR and immunofluorescence. The expression was compared between wild type and hemochromatosis (Hfe-/-) mouse retinas. The influence of iron on cholesterol homeostasis was studied by comparing the expression of the cholesterol efflux transporters ABCA1 and ABCG1 in retinas between wild type and Hfe-/- mice. Expression of these efflux transporters in ARPE-19 cells with and without exposure to 2,5-dihydroxybenzoic acid was also examined.
Bdh2 was expressed in all cell types in mouse retina (RPE, Muller cells, and neuronal cells), and its expression was increased in hemochromatosis. ABCA1 and ABCG1 were also expressed in all retinal cell types, and their expression was decreased in Hfe-/- retina. The decrease was 63% for ABCA1 and 39% for ABCG1. Treatment of ARPE-19 cells with 2,5-dihydroxyenzoic acid increased the expression of both efflux transporters (ABCA1: 1.8 fold; ABCG1: 3.9 fold).
The expression pattern of Bdh2 reveals that retina is able to synthesize the iron chelator 2,5-dihydroxybenzoic acid. Retinal Bdh2 is induced in hemochromatosis; increased production of the endogenous iron chelator might be a compensatory mechanism to protect the tissue from excessive iron. Iron regulates cholesterol homeostasis in retina. Iron overload associated with hemochromatosis decreases the expression of the cholesterol efflux transporters ABCA1 and ABCG1 whereas chelation of iron with 2,5-dihydroxybenzoic acid induces their expression. These studies show that iron is a regulator of cholesterol homeostasis in retina and RPE and that removal of cholesterol from retinal cells, including RPE, is impaired in hemochromatosis. Since excessive cholesterol is pro-inflammatory, we speculate that hemochromatosis might promote retinal inflammation via cholesterol accumulation.
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