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

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.

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

“…The APOE and ABCA1 genes have both been associated with Alzheimer’s disease and POAG, and are shown to interact with one another in Network 1 (Ananth et al, 2014; Liu et al, 2013). Ingenuity highlighted several studies which indicate that ABCA1 is needed for the proper metabolism of ApoE in the brain and preventing plaque formation and neurodegeneration (Hirsch-Reinshagen et al, 2004; Wahrle et al, 2004).…”

“…ABCA1 encodes for a cholesterol efflux transporter, which has been shown to play a role in Alzheimer’s disease and ocular diseases, including HTG and NTG (Ananth et al, 2014; Chen et al, 2014b; Liu et al, 2013). ABCA1 maintains cellular cholesterol homeostasis, by transferring cholesterol from cells (including neurons and glia) to the HDL molecule (Liu et al, 2013; Phillips, 2014).…”

“…Variants near ABCA1 have been shown to be significantly associated with the incidence of HTG, NTG, and OHT (Chen et al, 2014b; Hysi et al, 2014). Additionally, ABCA1 is expressed throughout the eye, including in RGCs, but to our knowledge no functional studies have been performed to determine how ABCA1 expression is directly related to the health of the optic nerve (Ananth et al, 2014; Gharahkhani et al, 2014). However, it has been shown that reduced expression of ABCA1 leads to accumulation of retinal cholesterol, and is associated with a pro-inflammatory state, contributing to the development of dry AMD in rodent models (Ananth et al, 2014).…”

“…Additionally, ABCA1 is expressed throughout the eye, including in RGCs, but to our knowledge no functional studies have been performed to determine how ABCA1 expression is directly related to the health of the optic nerve (Ananth et al, 2014; Gharahkhani et al, 2014). However, it has been shown that reduced expression of ABCA1 leads to accumulation of retinal cholesterol, and is associated with a pro-inflammatory state, contributing to the development of dry AMD in rodent models (Ananth et al, 2014). This lends credence to the idea that disruption of ABCA1 functionality could contribute to optic nerve inflammation and subsequent RGC death.…”

Iron and restless legs syndrome: treatment, genetics and pathophysiology

“…Moreover, various relations between iron and lipid metabolism have been identified recently by several lines of evidence, eg, by GWAS [66] on serum iron parameters, by the association of CSF ferritin with CSF apolipoprotein E and independently with the APOE ε4 genotype [67], or by the identification of gentisic acid (2,5-DHBA) as a siderophore for intracellular iron transport [68, 69]. …”