Liraglutide 透過GLP-1R/AMPK 通路保護視網膜色素上皮細胞對抗脂毒性與上皮間質轉化之探討

年齡相關性黃斑部病變（AMD）是導致老年人不可逆視力喪失的主要原因，其特徵為氧化壓力、脂質調節異常以及視網膜色素上皮（RPE）細胞功能障礙。AMD 的主要病理特徵之一是玻璃疣（drusen）的出現，這是一種由 RPE 分泌、富含脂質、蛋白質和細胞碎片的細胞外沉積物。這些沉積物會損害 RPE 的正常功能，促進慢性發炎反應並加速疾病進展。儘管近年對 AMD 發病機轉的認識有所進步，但目前針對 RPE 細胞脂質調節異常和氧化損傷的有效治療策略仍相當有限。本研究旨在評估類升糖素胜肽-1 受體促效劑（GLP-1RA）——利拉魯肽（liraglutide），對游離脂肪酸（FFA）引致之 ARPE-19 細胞（一種廣泛使用的 RPE 功能障礙體外模型）損傷的保護作用。研究結果顯示，FFA 處理會誘導細胞內脂質液滴（LD）堆積、產生氧化壓力以及引發上皮-間質轉型（EMT），這些過程皆與 AMD 的病理進展密切相關。透過高內涵影像分析、免疫細胞化學染色及分子生物學檢測證實，利拉魯肽共處理能顯著減少脂質液滴的堆積、緩解氧化壓力並有效抑制 EMT 的發生。在分子機轉方面，分析顯示利拉魯肽可顯著活化單磷酸腺苷活化蛋白激酶（AMPK），從而增強脂噬作用（lipophagy）並恢復細胞內的脂質穩態。此外，利拉魯肽還能調節外泌體（exosome）的分泌動態，藉由改變旁分泌訊號傳遞，進而減少鄰近細胞中的 EMT 標記物表達。綜上所述，本研究結果強調了利拉魯肽在應對 AMD 發病核心機轉（包括脂質調節異常、氧化壓力與 EMT）的關鍵潛力。本研究提供了創新且紮實的基礎醫學證據，支持未來將 GLP-1 受體促效劑開發為治療年齡相關性黃斑部病變的標靶藥物。

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly, characterized by oxidative stress, lipid dysregulation, and retinal pigment epithelium (RPE) dysfunction. One of the primary pathological hallmarks of AMD is the appearance of drusen, which are extracellular deposits rich in lipids, proteins, and cellular debris secreted by the RPE. These deposits impair the normal physiological functions of the RPE, promoting chronic inflammatory responses and accelerating disease progression. Despite recent advances in understanding the pathogenesis of AMD, effective therapeutic strategies targeting lipid dysregulation and oxidative damage in RPE cells remain highly limited.This study aimed to evaluate the protective effects of liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), against free fatty acid (FFA)-induced injury in ARPE-19 cells, a widely utilized in vitro model of RPE dysfunction. The results demonstrated that FFA treatment induced intracellular lipid droplet (LD) accumulation, generated oxidative stress, and triggered epithelial-mesenchymal transition (EMT), processes closely linked to the pathological progression of AMD. Confocal high-content analysis, immunocytochemistry, and molecular biology assays confirmed that co-treatment with liraglutide significantly reduced lipid droplet accumulation, alleviated oxidative stress, and effectively suppressed EMT occurrence.Mechanistically, analysis revealed that liraglutide significantly activated adenosine monophosphate-activated protein kinase (AMPK), thereby enhancing lipophagy and restoring intracellular lipid homeostasis. Furthermore, liraglutide modulated the secretion dynamics of exosomes, altering paracrine signaling to reduce the expression of EMT markers in neighboring cells.In conclusion, the findings highlight the critical potential of liraglutide in counteracting the core pathological mechanisms of AMD, including lipid dysregulation, oxidative stress, and EMT. This study provides innovative and solid basic medical evidence supporting the future development of GLP-1 receptor agonists as targeted therapeutics for age-related macular degeneration.