Transcriptome-based reconstructions from the murine knockout suggest involvement of the urate transporter, URAT1 (slc22a12), in novel metabolic pathways

URAT1 (slc22a12) was identified as the transporter responsible for renal reabsorption of the medically important compound, uric acid. However, subsequent studies have indicated that other transporters make contributions to this process, and that URAT1 transports other organic anions besides urate (including several in common with the closely related multi-specific renal organic anion transporters, OAT1 (slc22a6) and OAT3 (slc22a8)). These findings raise the possibility that urate transport is not the sole physiological function of URAT1. We previously characterized mice null for the murine ortholog of URAT1 (mURAT1; previously cloned as RST), finding a relatively modest decrement in urate reabsorptive capacity. Nevertheless, there were shifts in the plasma and urinary concentrations of multiple small molecules, suggesting significant metabolic changes in the knockouts. Although these molecules remain unidentified, here we have computationally delineated the biochemical networks consistent with transcriptomic data from the null mice. These analyses suggest alterations in the handling of not only urate but also other putative URAT1 substrates comprising intermediates in nucleotide, carbohydrate, and steroid metabolism. Moreover, the analyses indicate changes in multiple other pathways, including those relating to the metabolism of glycosaminoglycans, methionine, and coenzyme A, possibly reflecting downstream effects of URAT1 loss. Taken together with the available substrate and metabolomic data for the other OATs, our findings suggest that the transport and biochemical functions of URAT1 overlap those of OAT1 and OAT3, and could contribute to our understanding of the relationship between uric acid and the various metabolic disorders to which it has been linked.
Highlights • URAT1 handles multiple substrates suggesting functions beyond urate transport • We determined metabolic constraints of gene expression changes in URAT1 null mice • These suggest URAT1 involvement in multiple bioenergtic and biosynthetic pathways