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

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.

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Publication Details

Journal
Nature Communications
Published
2024-08-12
DOI
https://doi.org/10.1038/s41467-024-51174-3
Citations
10
Primary Topic
Metabolomics and Mass Spectrometry Studies
Type
article
Field-Weighted Citation Impact
2.34

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article

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

Edward D. Karoly, Jan Spaas, Nora Scherer, Veronica L. Li et al.
10 citations
Nature Communications
Metabolomics and Mass Spectrometry Studies
2.34
article

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

Edward D. Karoly, Jan Spaas, Nora Scherer, Veronica L. Li, Jonathan Z. Long, Alan Sheng-Hwa Tung, Pascal Schlosser, Shuke Xiao, Anna Köttgen, Amanda L. Wiggenhorn
article en
10 citations

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.

Nature CommunicationsVol. 15(1)
Johns Hopkins University (US), University of Freiburg (DE), Neurosciences Institute (US), Cardiovascular Institute of the South (US), Metabolon (United States) (US), Stanford Medicine (US), Stanford University (US)
American Heart Association, Stanford Diabetes Research Center, Deutsche Forschungsgemeinschaft, Ono Pharma Foundation, National Institutes of Health, Wu Tsai Neurosciences Institute, Stanford University
Zero hunger
Openalex Percentile: Top 11%
Metabolomics and Mass Spectrometry Studies
2.34
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