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

Veronica L. Li, Shuke Xiao, Pascal Schlosser, Nora Scherer, Amanda L. Wiggenhorn, Jan Spaas, Alan Sheng-Hwa Tung, Edward D. Karoly, Anna Köttgen and Jonathan Z. Long ()
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Veronica L. Li: Stanford University School of Medicine
Shuke Xiao: Stanford University School of Medicine
Pascal Schlosser: University of Freiburg
Nora Scherer: University of Freiburg
Amanda L. Wiggenhorn: Stanford University School of Medicine
Jan Spaas: Stanford University School of Medicine
Alan Sheng-Hwa Tung: Stanford University School of Medicine
Edward D. Karoly: Inc.
Anna Köttgen: University of Freiburg
Jonathan Z. Long: Stanford University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51174-3

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