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

• Published in: Nature communications 2024-08, Vol.15 (1), p.6895-10, Article 6895
• Main Authors: Li, Veronica L., Xiao, Shuke, Schlosser, Pascal, Scherer, Nora, Wiggenhorn, Amanda L., Spaas, Jan, Tung, Alan Sheng-Hwa, Karoly, Edward D., Köttgen, Anna, Long, Jonathan Z.
• Format: Article
• Language: English
• Subjects: 42/41; 631/208/457/649; 631/45/320; 64/60; 82/58; Ablation; Adult; Animals; Body weight; Cell culture; Cell membranes; Efflux; Excretion; Female; Food intake; HEK293 Cells; Humanities and Social Sciences; Humans; Kidney - metabolism; Kidneys; Lactates - blood; Lactates - metabolism; Lactates - urine; Lactic acid; Male; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Phenylalanine; Phenylalanine - blood; Phenylalanine - metabolism; Phenylalanine - urine; Renal Elimination; Renal function; Science; Science (multidisciplinary); Urine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51174-3

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. The lactate metabolite N-lactoyl-phenylalanine (Lac-Phe) plays a role in suppressing food intake and body weight. Here, the authors identify kidney transporters responsible for the renal excretion of Lac-Phe. This discovery highlights a pathway for Lac-Phe regulation in mice and humans.