Vitamin C transporter SVCT1 serves a physiological role as a urate importer: functional analyses and in vivo investigations

• Published in: Pflügers Archiv 2023-04, Vol.475 (4), p.489-504
• Main Authors: Toyoda, Yu, Miyata, Hiroshi, Uchida, Naohiro, Morimoto, Keito, Shigesawa, Ryuichiro, Kassai, Hidetoshi, Nakao, Kazuki, Tomioka, Naoko H., Matsuo, Hirotaka, Ichida, Kimiyoshi, Hosoyamada, Makoto, Aiba, Atsu, Suzuki, Hiroshi, Takada, Tappei
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Ascorbic acid; Ascorbic Acid - metabolism; Biological Transport; Biomedical and Life Sciences; Biomedicine; Cell Biology; CRISPR; Gout; Human Physiology; Humans; Hyperuricemia; Ion Channels; Ion Channels, Receptors and Transporters; Mammals - metabolism; Mice; Molecular Medicine; Neurosciences; Organic Anion Transporters - metabolism; Oxidants; Receptors; Receptors and Transporters; Sodium-Coupled Vitamin C Transporters - genetics; Sodium-Coupled Vitamin C Transporters - metabolism; Substrate specificity; Urate oxidase; Uric acid; Uric Acid - metabolism; Vitamin C
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-023-02792-1

Uric acid, the end product of purine metabolism in humans, is crucial because of its anti-oxidant activity and a causal relationship with hyperuricemia and gout. Several physiologically important urate transporters regulate this water-soluble metabolite in the human body; however, the existence of latent transporters has been suggested in the literature. We focused on the Escherichia coli urate transporter YgfU, a nucleobase-ascorbate transporter (NAT) family member, to address this issue. Only SLC23A proteins are members of the NAT family in humans. Based on the amino acid sequence similarity to YgfU, we hypothesized that SLC23A1, also known as sodium-dependent vitamin C transporter 1 (SVCT1), might be a urate transporter. First, we identified human SVCT1 and mouse Svct1 as sodium-dependent low-affinity/high-capacity urate transporters using mammalian cell-based transport assays. Next, using the CRISPR-Cas9 system followed by the crossing of mice, we generated Svct1 knockout mice lacking both urate transporter 1 and uricase . In the hyperuricemic mice model, serum urate levels were lower than controls, suggesting that Svct1 disruption could reduce serum urate. Given that Svct1 physiologically functions as a renal vitamin C re-absorber, it could also be involved in urate re-uptake from urine, though additional studies are required to obtain deeper insights into the underlying mechanisms. Our findings regarding the dual-substrate specificity of SVCT1 expand the understanding of urate handling systems and functional evolutionary changes in NAT family proteins.