Gout Causing ABCG2 Mutation Results in Intestinal Net Urate Transport Defect, Hyperuricemia, & Altered Metabolic Phenotype
Authors: Kazi Mirajul Hoque , Lewis Raychel M , Woodward Owen M 
Published: February 2021

Hyperuricemia causes gout and is implicated in metabolic syndrome, impaired glucose tolerance/type 2 diabetes, and hypertension. Individuals carrying a common loss of function variant in the dominant secretory transporter, Q141K ABCG2, have significantly increased serum urate and gout risk yet their renal fractional excretion of urate (FEUA) is largely unchanged. However, the role in ABCG2 and other urate transporters in extra‐renal secretion remains mostly unexplored. Here we sought to identify the role of ABCG2 in trans‐epithelial urate transport in the intestines and contribution of intestinal ABCG2 dysfunction to hyperuricemia and urate related phenotypes. First, we established a genetic mouse model of the human ABCG2 Q141K variant (Q140K in mouse) using CRISPR Cas9 gene editing techniques on a C57BL6 mouse background. As compared to control mice, mice possessing the Q140K Abcg2 allele were profoundly hyperuricemic, yet exhibited only modest changes in renal excretion of urate, similar to what has been reported previously in humans. To explore mechanisms, we first mapped prominent urate transporters ABCG2 and SLC2A9 along the mouse intestine and found the highest levels in the jejunum and ileum. Localization of the wild type ABCG2 protein was exclusive to the brush border (apical membrane) of the villus cells, seemingly optimized to facilitate urate secretion(JUAsm). Interestingly, we also found evidence that SLC2A9 localized predominantly to the basolateral enterocyte membrane. In Ussing chamber experiments, we functionally confirmed basolateral localization of the electrogenic SLC2A9 transporter by observing basolateral but not apical addition of 0.5 mM urate significantly stimulated Isc (24 ± 3μA/cm2) in comparison with control (10± 2.2 μA/cm2). Further, treatment of the serosal membrane with SLC2A9 inhibitors tranilast and pCMBS partially inhibited JUAsm flux of urate in an intestinal loop model. In contrast to the WT controls, Q140K mice demonstrated a significant decrease of apical ABCG2 protein abundance, with commiserate, significant loss of unidirectional urate transport (JUAsm) in jejunal loops (Q140K, 24 ± 3.38 μM/cm2/min; WT, 46 ± 1.50 μM/cm2/min), resulting in conversion of net urate secretion (−18 ± 4 μM/cm2/min) to net urate absorption (+5.99 ± 2.2 μM/cm2/min). Interestingly, these significant alterations in intestinal urate secretion in the Q140K mice correlated with evidence of altered serum insulin and non‐fasting glucose levels, not unlike what has been previously reported in mice lacking intestinal SLC2A9 strongly suggesting the establishment of SLC2A9 and ABCG2 as the intestinal urate excretion pathway.CONCLUSIONSOur findings demonstrate the pathophysiology of one of the most common hyperuricemia and gout risk variants, Q141K ABCG2, primarily affects the urate secretion in the gut, causing hyperuricemia and alterations in insulin and glucose levels with important implications for human disease.Support or Funding InformationNIDDK RO1DK114091AHA14SDG18060004This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.