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

Author

Listed:
  • Tae Jun Lee

    (Washington University in St. Louis School of Medicine
    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
    University of Tokyo)

  • 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
    BioTechMed-Graz)

  • Christina Christoffersen

    (University of Copenhagen
    University of Copenhagen)

  • Ali Javaheri

    (Washington University in St. Louis School of Medicine
    John Cochran VA Hospital)

  • Rajendra S. Apte

    (Washington University in St. Louis School of Medicine
    Washington University in St. Louis School of Medicine)

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.

Suggested Citation

  • Tae Jun Lee & Andrea Santeford & Kristen M. Pitts & Carla Valenzuela Ripoll & Ryo Terao & Zhen Guo & Mualla Ozcan & Dagmar Kratky & Christina Christoffersen & Ali Javaheri & Rajendra S. Apte, 2025. "Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60830-1
    DOI: 10.1038/s41467-025-60830-1
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    References listed on IDEAS

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    1. James T. Handa & Cathy Bowes Rickman & Andrew D. Dick & Michael B. Gorin & Joan W. Miller & Cynthia A. Toth & Marius Ueffing & Marco Zarbin & Lindsay A. Farrer, 2019. "A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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