Regulation of the cholesterol efflux transporters ABCA1 and ABCG1 in retina in hemochromatosis and by the endogenous siderophore 2,5-dihydroxybenzoic acid

Sudha Ananth, Jaya P. Gnana-Prakasam, Yangzom D. Bhutia, Rajalakshmi Veeranan-Karmegam, Pamela M. Martin, Sylvia B. Smith, Vadivel Ganapathy

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)603-612
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • Cholesterol transport
  • Hemochromatosis
  • Mammalian siderophore
  • Retinal pigment epithelial cells
  • β-Hydroxybutyrate dehydrogenase-2

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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