Dysregulated lipid metabolism in a retinal pigment epithelial cell model and serum of patients with age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness, characterized by retinal pigment epithelium (RPE) dysfunction, extracellular deposit formation, and disrupted lipid metabolism. Understanding the molecular changes underlying AMD is essential for identifying diagnostic markers and therapeutic targets. RESULTS: This multiomic study employed a primary RPE culture model to investigate age-related changes associated with AMD. Over 25 weeks, RPE cells exhibited phenotypic deterioration, including depigmentation, cell shape deformation, and barrier integrity loss, accompanied by extracellular deposit formation. Transcriptomic analysis revealed dysregulation of genes involved in lipid metabolism, including pathways for cholesterol transport, glycerophospholipids, and ceramide biosynthesis. Metabolomic profiling further identified significant changes in glycerophospholipid and sphingolipid metabolism, highlighting a decline in phospholipid species and ceramide accumulation. Serum analysis of AMD patients revealed altered levels of 18 lipids identified in RPE cultures. Four lipids showed significant differences compared to controls: GlcCer(d16:1/18:0) (1.23-fold increase, adj. p value < 0.001), PE(19:1(9Z)/22:2(13Z,16Z)) (0.34-fold decrease, adj. p value < 0.001), PE(15:0/20:3(5Z,8Z,11Z)) (0.66-fold decrease, adj. p value < 0.05), and PC(22:2(13Z,16Z)/13:0) (0.71-fold decrease, adj. p value < 0.05). These findings underscore the systemic nature of lipid dysregulation in AMD and the translational relevance of the RPE model. CONCLUSIONS: This study highlights the significant role of lipid metabolism dysregulation in AMD pathogenesis. The consistent lipidomic alterations observed in RPE cultures and AMD patient serum reinforce their potential as biomarkers for disease progression and therapeutic targets. These findings provide a robust framework for understanding AMD-associated lipid metabolism changes and their systemic impact.