Regulation of cellular sphingolipid metabolism by lipid-protein adducts and genetic variants associated with age-related macular degeneration

LIEBISCH, GERHARD; SKERKA, CHRISTINE; PUJOL LEREIS, LUCIANA M.; ZIPFEL, PETER F.; LIN, YUCHEN; WEBER, BERNHARD H. F.

Córdoba

Congreso; XXXIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

Sociedad Argentina de Investigación en Neurociencias

Age-related macular degeneration (AMD) is a common sight-threatening condition with complex etiology. Genetic, environmental, and diet factors are associated with AMD risk. Oxidative damage is thought to play a key role in the causality of AMD, and by-products of lipid peroxidation, such as malondialdehyde-acetaldehyde (MAA) adducts, were shown to be highly elevated in AMD retinas. We previously reported increased levels of serum ceramides in AMD patients compared to controls, and observed that genetic variant rs1061170 (p.Y402H) in the complement factor H (CFH)/factor H-like protein 1 (FHL-1) gene correlates with Cer d18:1/16:0 levels in AMD. The aim of this study was to evaluate the cellular sphingolipid metabolism under treatment with MAA adducts, and the modulation by FHL-1, an alternative splicing isoform of CFH. For this purpose, we evaluated cell survival, gene expression, and sphingolipid levels in WERI-Rb1 and ARPE-19 cells exposed to MAA-BSA or BSA. In the concentrations evaluated, WERI-Rb1 cells were more affected than ARPE-19 cells, with a decrease in survival, upregulation of ceramide synthesis genes, and higher ceramide levels under MAA treatment. Notably, WERI-Rb1 cells exposed to the non-risk isoform FHL-1:Y402, but not the AMD risk associated isoform FHL-1:H402 or CFH, revealed a downregulation of ceramide synthesis genes. Together, our findings suggest that ceramide levels are influenced by AMD associated risk variants and oxidative stress by-products.