Álvarez-Barrios Ana, Álvarez Lydia, Sáenz de Santa María Pilar, García Montserrat, Álvarez-Buylla Jorge R, Pereiro Rosario, González-Iglesias Héctor
Fundación de Investigación Oftalmológica, Oviedo, Spain.
Department of Physical and Analytical Chemistry, University of Oviedo, Oviedo, Spain.
BMC Biol. 2025 Apr 12;23(1):96. doi: 10.1186/s12915-025-02198-8.
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.
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.
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.
年龄相关性黄斑变性（AMD）是导致失明的主要原因，其特征为视网膜色素上皮（RPE）功能障碍、细胞外沉积物形成以及脂质代谢紊乱。了解AMD潜在的分子变化对于识别诊断标志物和治疗靶点至关重要。
这项多组学研究采用原代RPE培养模型来研究与AMD相关的年龄相关性变化。在超过25周的时间里，RPE细胞表现出表型恶化，包括色素脱失、细胞形状变形和屏障完整性丧失，并伴有细胞外沉积物形成。转录组分析显示参与脂质代谢的基因失调，包括胆固醇转运、甘油磷脂和神经酰胺生物合成途径。代谢组学分析进一步确定了甘油磷脂和鞘脂代谢的显著变化，突出了磷脂种类的减少和神经酰胺的积累。对AMD患者的血清分析显示，在RPE培养物中鉴定出的18种脂质水平发生了改变。与对照组相比，四种脂质显示出显著差异：葡萄糖神经酰胺（GlcCer(d16:1/18:0)）（增加1.23倍，校正p值<0.001）、磷脂酰乙醇胺（PE(19:1(9Z)/22:2(13Z,16Z))）（减少0.34倍，校正p值<0.001）、磷脂酰乙醇胺（PE(15:0/20:3(5Z,8Z,11Z))）（减少0.66倍，校正p值<0.05）和磷脂酰胆碱（PC(22:2(13Z,16Z)/13:0)）（减少0.71倍，校正p值<0.05）。这些发现强调了AMD中脂质失调的系统性本质以及RPE模型的转化相关性。
本研究突出了脂质代谢失调在AMD发病机制中的重要作用。在RPE培养物和AMD患者血清中观察到的一致的脂质组学改变增强了它们作为疾病进展生物标志物和治疗靶点的潜力。这些发现为理解与AMD相关的脂质代谢变化及其系统性影响提供了一个有力的框架。
