HGLUT9 as a novel urate transporter: its role in liver urate handling and functional study of SLC2A9 SNPs

Abstract

In humans, urate is the final product of purine breakdown in the liver which releases urate into the circulation and the intestine and kidney regulate its excretion. Humans have a high circulating level of urate and small deviations are associated with a variety of metabolic diseases. A genome‐wide association scan correlated SNPs within the SLC2A9 gene, for the hexose transporter GLUT9, with hyperuricemia. This resulted in the identification of this protein as a high capacity urate transporter, which can exchange intracellular urate for extracellular glucose (1). Urate is an organic anion and voltage clamp experiments with GLUT9 expressed in Xenopus oocytes showed that its transport is electrogenic. Immunohistochemistry showed that all of the GLUT9 SNP mutants were expressed in the oocyte plasma membrane and flux studies indicate that all are functional. GLUT9 is expressed in the hepatocyte basolateral membrane and these data support the hypothesis that GLUT9 mediates the efflux of urate down its electrical gradient. Further, in the absence of direct functional effects of the SNPs, it appears that more complex effects of these mutations, perhaps on cytoskeletal interactions or yet to be identified regulatory mechanisms, affect the activity of GLUT9.1. Mark J. Caulfield, et al (2008) SLC2A9 is a high capacity urate transporter in man. PLoS Medicine 5(10):e197.Supported by the Canadian Breast Cancer Foundation.