Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration

Abstract

Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 (ABCA1), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the ABCA1 AMD risk-conferring allele decreases ABCA1 expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

“…Several studies to date have examined the phenotype of tissue-specific knockdown of downstream target genes of the LXR, including ABCA1 in photoreceptor and RPE cells (80,81). In the absence of Abca1 in mouse photoreceptors, there is accumulation of neutral lipid-rich subretinal debris and Aif1 + subretinal cells, along with compromise in visual function (81) while the absence of Abca1 in the mouse RPE demonstrated retinal degenerative changes, including significant RPE and retinal degeneration concomitant with RPE lipoidal degeneration, a phenotype also seen in our Nr1h2 -/mice (80). Given previous findings that Abca1 levels are affected more so in the absence of the β-isoform than α-isoform, it is plausible that downstream effectors other than Abca1 may be involved in the accumulation of lipids extracellular to RPE cells (e.g., the lipid-rich drusen phenotype).…”

Cholesterol homeostasis in the vertebrate retina: biology and pathobiology

“…ABCA1 and ABCG1 expression has been reported for the RPE, in addition to the neural retina (80,128,133). CYP27A1/CYP46A1 global double-knockout mice (CYP27A1 -/--CYP46A1 -/-) exhibit elevation in retinal cholesteryl ester content in lipid droplets.…”

“…Future investigations into ABC transporter activity in CYP27A1 -/--CYP46A1 -/--ACAT1 -/and CYP27A1 -/--CYP46A1 -/models may provide additional new insights into the retinal cholesterol efflux mechanism. The accumulation of cholesteryl esters in the retina and RPE in the above discussed animal models has been observed using either Oil Red-O staining, filipin labeling and fluorescence imaging of retinal tissue sections (plus and minus cholesteryl esterase treatment), as well as transmission electron microscopy (124,133,162).…”

Dyslipidemia in retinal metabolic disorders

“…Genome‐wide association studies also identify several HDL cholesterol genes associated with AMD susceptibility, including genes encoding ATP‐binding cassette transporter A1 ( ABCA1 ) , cholesteryl ester transfer protein ( CETP ) , apolipoprotein E ( APOE ), hepatic lipase C ( LIPC ), and lipoprotein lipase precursor (LPL) (Chen et al , ; Neale et al , ; Fritsche et al , , ). Impaired ABCA1‐mediated cholesterol efflux in mouse RPE cells or subretinal macrophages induces lipid accumulation and retinal degeneration (Lyssenko et al , ; Storti et al , ). ApoE is important for the transport of lipids across cell membranes and is highly expressed by RPE cells.…”