Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism

Tae Jun Lee, Andrea Santeford, Kristen M. Pitts, Carla Valenzuela Ripoll, Ryo Terao, Zhen Guo, Mualla Ozcan, Dagmar Kratky, Christina Christoffersen, Ali Javaheri () and Rajendra S. Apte ()
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Tae Jun Lee: Washington University in St. Louis School of Medicine
Andrea Santeford: Washington University in St. Louis School of Medicine
Kristen M. Pitts: Washington University in St. Louis School of Medicine
Carla Valenzuela Ripoll: Washington University in St. Louis School of Medicine
Ryo Terao: Washington University in St. Louis School of Medicine
Zhen Guo: Washington University in St. Louis School of Medicine
Mualla Ozcan: Washington University in St. Louis School of Medicine
Dagmar Kratky: Medical University of Graz
Christina Christoffersen: University of Copenhagen
Ali Javaheri: Washington University in St. Louis School of Medicine
Rajendra S. Apte: Washington University in St. Louis School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improves retinal pigment epithelium (RPE) function and lipotoxicity in an S1P- and S1P receptor 3-dependent manner. Ultrastructural evidence of enhanced melanosome-lipid droplet interactions led us to hypothesize and demonstrate that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. RPE-specific knockout of lysosomal acid lipase recapitulates features of AMD. Our study defines a novel role for ApoM/S1P signaling in AMD driven by RPE lipotoxicity, mediated by cell-autonomous lysosomal lipid catabolism.

Date: 2025
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DOI: 10.1038/s41467-025-60830-1

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