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SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans

Author

Listed:
  • Veronica L. Li

    (Stanford University School of Medicine
    Stanford University
    Stanford University
    Stanford University)

  • Shuke Xiao

    (Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Pascal Schlosser

    (University of Freiburg
    Johns Hopkins University Bloomberg School of Public Health
    University of Freiburg)

  • Nora Scherer

    (University of Freiburg
    University of Freiburg)

  • Amanda L. Wiggenhorn

    (Stanford University School of Medicine
    Stanford University
    Stanford University
    Stanford University)

  • Jan Spaas

    (Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Alan Sheng-Hwa Tung

    (Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Edward D. Karoly

    (Inc.)

  • Anna Köttgen

    (University of Freiburg
    Johns Hopkins University Bloomberg School of Public Health
    University of Freiburg)

  • Jonathan Z. Long

    (Stanford University School of Medicine
    Stanford University
    Stanford University
    Stanford University)

Abstract

N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating SLC17A1/3-dependent de-coupling of urine and plasma Lac-Phe pools. Together, these data establish SLC17A1/3 family members as the physiologic urine Lac-Phe transporters and uncover a biochemical pathway for the renal excretion of this signaling metabolite.

Suggested Citation

  • Veronica L. Li & Shuke Xiao & Pascal Schlosser & Nora Scherer & Amanda L. Wiggenhorn & Jan Spaas & Alan Sheng-Hwa Tung & Edward D. Karoly & Anna Köttgen & Jonathan Z. Long, 2024. "SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51174-3
    DOI: 10.1038/s41467-024-51174-3
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    References listed on IDEAS

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    3. Veronica L. Li & Yang He & Kévin Contrepois & Hailan Liu & Joon T. Kim & Amanda L. Wiggenhorn & Julia T. Tanzo & Alan Sheng-Hwa Tung & Xuchao Lyu & Peter-James H. Zushin & Robert S. Jansen & Basil Mic, 2022. "An exercise-inducible metabolite that suppresses feeding and obesity," Nature, Nature, vol. 606(7915), pages 785-790, June.
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