Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism
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.
Authors
- Tae Jun Lee (ORCID: https://orcid.org/0000-0003-2699-2573)
- Ali Javaheri (ORCID: https://orcid.org/0000-0001-6657-331X)
- Kristen Pitts (ORCID: https://orcid.org/0000-0001-7049-0883)
- Zhen Guo (ORCID: https://orcid.org/0000-0002-8421-4852)
- Mualla Özcan (ORCID: https://orcid.org/0000-0002-1763-5454)
- Dagmar Kratky (ORCID: https://orcid.org/0000-0003-1357-7573)
- Andrea Santeford (ORCID: https://orcid.org/0000-0002-7691-6213)
- Ryo Terao (ORCID: https://orcid.org/0000-0001-6182-4343)
- Christina Christoffersen (ORCID: https://orcid.org/0000-0003-3751-5203)
- Rajendra S. Apte (ORCID: https://orcid.org/0000-0003-2281-2336)
- Carla Valenzuela Ripoll (ORCID: https://orcid.org/0000-0002-6177-5227)
Institutions
- University of Copenhagen (DK)
- Medical University of Graz (AT)
- Washington University in St. Louis (US)
- Rigshospitalet (DK)
- BioTechMed-Graz (AT)
- John Cochran VA Medical Center (US)
- The University of Tokyo (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1038/s41467-025-60830-1
- Citations
- 3
- Primary Topic
- Retinal Diseases and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.12
Funders
- Research to Prevent Blindness
- Children's Discovery Institute
- Starr Foundation
- Carl Marshall and Mildred Almen Reeves Foundation
- VitreoRetinal Surgery Foundation
- Austrian Science Fund
- National Institutes of Health
- Washington University School of Medicine in St. Louis
- National Heart, Lung, and Blood Institute
- National Eye Institute