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; Jonathan Z Long

doi:10.1038/s41467-024-51174-3

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

Nat Commun. 2024 Aug 12;15(1):6895. doi: 10.1038/s41467-024-51174-3.

Authors

Veronica L Li^{1

2

3

4}, Shuke Xiao^{1

3

4}, Pascal Schlosser^{5

6

7}, Nora Scherer^{5

8}, Amanda L Wiggenhorn^{1

2

3

4}, Jan Spaas^{1

3

4}, Alan Sheng-Hwa Tung^{1

3

4}, Edward D Karoly⁹, Anna Köttgen^{5

6

7}, Jonathan Z Long^{10

11

12

13

14}

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Chemistry, Stanford University, Stanford, CA, USA.
³ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁴ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁵ Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
⁶ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Centre for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, Freiburg, Germany.
⁸ Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
⁹ Metabolon, Inc., Morrisville, NC, USA.
¹⁰ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹¹ Sarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected].
¹² Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. [email protected].
¹³ The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. [email protected].
¹⁴ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. [email protected].

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.

MeSH terms

Adult
Animals
Female
HEK293 Cells
Humans
Kidney* / metabolism
Lactates / blood
Lactates / metabolism
Lactates / urine
Male
Mice
Mice, Inbred C57BL
Mice, Knockout*
Phenylalanine / blood
Phenylalanine / metabolism
Phenylalanine / urine
Renal Elimination

Substances

Lactates
Phenylalanine
N-lactoyl-phenylalanine

Abstract

MeSH terms

Substances

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