Hyperuricemia in acute gastroenteritis is caused by decreased urate excretion via ABCG2

Abstract

To clarify the physiological and pathophysiological roles of intestinal urate excretion via ABCG2 in humans, we genotyped ABCG2 dysfunctional common variants, Q126X (rs72552713) and Q141K (rs2231142), in end-stage renal disease (hemodialysis) and acute gastroenteritis patients, respectively. ABCG2 dysfunction markedly increased serum uric acid (SUA) levels in 106 hemodialysis patients (P = 1.1 × 10−4), which demonstrated the physiological role of ABCG2 for intestinal urate excretion because their urate excretion almost depends on intestinal excretion via ABCG2. Also, ABCG2 dysfunction significantly elevated SUA in 67 acute gastroenteritis patients (P = 6.3 × 10−3) regardless of the degree of dehydration, which demonstrated the pathophysiological role of ABCG2 in acute gastroenteritis. These findings for the first time show ABCG2-mediated intestinal urate excretion in humans, and indicates the physiological and pathophysiological importance of intestinal epithelium as an excretion pathway besides an absorption pathway. Furthermore, increased SUA could be a useful marker not only for dehydration but also epithelial impairment of intestine.

Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all-cause mortality in hemodialysis patients

“…ABCG2 knockout mice showed decreased intestinal excretion of uric acid [5,34]. ABCG2-mediated intestinal urate excretion was also evidenced in a human study [11]. The present results showed that serum uric acid levels differed according to the estimated levels of ABCG2 function in hemodialysis patients.…”

“…Future studies are needed to evaluate the association between uric acid and mortality. Since ABCG2 is the main urate transporter in both the kidney and intestine [3,5,11,18,30,31], previous studies reported that dysfunctional ABCG2 gene polymorphisms are associated with hyperuricemia by decreasing urate excretion [3,32]. In addition, ABCG2 is also associated with the prevalence and onset of gout [3,6].…”

“…Genomic DNA was extracted from whole peripheral blood cells. Genotyping of ABCG2 dysfunctional variants (Q126X and Q141K) was performed using the TaqMan method (Life Technologies Corporation, Carlsbad, CA, USA) with a Light Cycler 480 (Roche Diagnostics, Mannheim, Germany), as previously described [11,18]. Custom TaqMan assay probes were designed as follows: for Q126X, VIC-CCA CTA ATA CTT ACT TGT ACCAC and FAM-CCA CTA ATA CTT ACT TAT ACCAC; and for Q141K, VIC-CTG CTG AGA ACT GTA AGT T and FAM-CTG CTG AGA ACT TTA AGT T.…”

“…In addition, hyperuricemia is a risk factor for cardiovascular disease (CVD) in the general population [9,10]. Furthermore, a previous study reported that serum uric acid levels were dependent on ABCG2 polymorphisms [3,6,11]. These results suggest that ABCG2 plays a prominent role in uric acid homeostasis.…”

IL‐1β functionally attenuates ABCG2 and PDZK1 expression in HK‐2 cells partially through NF‐ĸB activation

“…Paradoxically, IL‐1β‐induced ABCG2 dysfunction augmented the urate excretion in tubular epithelium cells. In mice‐ (Ichida et al, ) and patient‐ (Matsuo et al, ; Matsuo et al, ) based studies, the increase of the serum urate level and renal urate excretion was explicated that ABCG2 downregulation led to the decrease of intestinal urate excretion. The normal net urate excretion was determined by urate reabsorption and secretion on the membrane of tubular epithelial cell.…”