gms | German Medical Science

Since the RPE has to internalize large amounts of shed tips of photoreceptor outer segments every day, it requires an efficient intracellular system to handle, metabolize and/or dispose lipids. Several genes involved in lipid metabolism including the ATP-binding cassette transporter A1 (ABCA1) have been linked to AMD suggesting that an impaired lipid handling contributes to disease development. Using an in vitro system, we show that ABCA1 localizes to both sides of polarized RPE cells and is required for efflux of photoreceptor outer segment-derived cholesterol to extracellular acceptor proteins as a first step in high-density lipoprotein (HDL) biosynthesis. Mice with an RPE-specific deletion of Abca1 and its partner Abcg1 showed strong accumulation of lipids, especially of cholesteryl esters, in the RPE, reduced function of the RPE and the retina, inflammation, as well as age-dependent RPE and photoreceptor degeneration. Inactivation of Abca1 but not of Abcg1 alone was sufficient to increase the lipid load in the RPE. Expression of ABCA1 in cell lines from human patients carrying the ABCA1 AMD risk-conferring allele was reduced potentially identifying the molecular mechanism that might explain the genetic risk for AMD in these patients. Our data strengthen the hypothesis that efficient lipid efflux from the RPE is required to maintain tissue homeostasis and suggest a pathogenic contribution of locally reduced ABCA1 function to AMD.