Abstract
Sphingolipids are bioactive molecules associated with oxidative stress, inflammation, and neurodegenerative diseases, but poorly studied in the context of age-related macular degeneration (AMD), a prevalent sight-threatening disease of the ageing retina. Here, we found higher serum levels of hexosylceramide (HexCer) d18:1/16:0 in patients with choroidal neovascularization (CNV) and geographic atrophy (GA), two manifestations of late stage AMD, and higher ceramide (Cer) d18:1/16:0 levels in GA patients. A sensitivity analysis of genetic variants known to be associated with late stage AMD showed that rs1061170 (p.Y402H) in the complement factor H (CFH) gene influences the association of Cer d18:1/16:0 with GA. To understand the possible influence of this genetic variant on ceramide levels, we established a cell-based assay to test the modulation of genes in the ceramide metabolism by factor H-like protein 1 (FHL-1), an alternative splicing variant of CFH that also harbors the 402 residue. We first showed that malondialdehyde-acetaldehyde adducts, an oxidation product commonly found in AMD retinas, induces an increase in ceramide levels in WERI-Rb1 cells in accordance with an increased expression of ceramide synthesis genes. Then, we observed that cells exposed to the non-risk FHL-1:Y402, but not the risk associated variant FHL-1:H402 or full-length CFH, downregulated ceramide synthase 2 and ceramide glucosyltransferase gene expression. Together, our findings show that serum ceramide and hexosylceramide species are altered in AMD patients and that ceramide levels may be influenced by AMD associated risk variants.
Highlights
Age-related macular degeneration (AMD) is a multifactorial progressive disease of the central retina and the leading cause of blindness in developed countries in people over 60 years of age [1]
In the joint late stage age-related macular degeneration (AMD) analysis, we found higher levels of hexosylceramide (HexCer) d18:1/16:0 in AMD patients compared to controls (Table 2)
We show for the first time that levels of ceramide species are significantly elevated in serum of late stage AMD patients compared to healthy control individuals in a population based study
Summary
Age-related macular degeneration (AMD) is a multifactorial progressive disease of the central retina and the leading cause of blindness in developed countries in people over 60 years of age [1]. With lower effect sizes, several lipid pathway genes have been significantly associated with AMD risk, including apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP), hepatic triglyceride lipase (LIPC), ATP-binding cassette transporter A-1 (ABCA1), ABCA7, lipoprotein lipase (LPL), and fatty acid desaturase 1 (FADS1) [9,10,11]. The fact that lipoproteins and cholesterol are major constituents of drusen has motivated previous studies to investigate into circulatory lipid levels of AMD patients. Higher levels of total n3 fatty acids, α-linolenic acid (18:3-n3) and long chain n3 fatty acids were associated with a reduced risk for late AMD, with no significant association of docosahexaenoic acid (22:6-n3) or eicosapentanoic acid (20:5-n3) [29]. Besides unesterified cholesterol and triglycerides, other lipid classes present in lipoproteins are phospholipids, cholesteryl esters, and sphingolipids such as sphingomyelins (SM) and ceramides [31]
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