Facilitative glucose transporter 9, a unique hexose and urate transporter

Abstract

is a novel, facilitative glucose transporter isoform that exists as two alternative splice variants encoding two proteins that differ in their NH 2-terminal sequence (GLUT9a and GLUT9b). Both forms of GLUT9 protein and mRNA are expressed in the epithelia of various tissues; however, the two splice variants are expressed differentially within polarized cells, with GLUT9a localized predominantly on the basolateral surfaces and GLUT9b expressed on apical surfaces. Protein expression of GLUT9 drops under conditions of starvation but increases with addition of glucose and under hyperglycemic conditions. The substrate specificity of GLUT9 is unique since, in addition to transporting hexose sugars, it also is a high-capacity uric acid transporter. Several recent large-scale human genetic studies show a correlation between SNPs mapped to GLUT9 and the serum uric acid levels in several different cohorts. The relationship between GLUT9 and uric acid is highly clinically significant. Elevated uric acid levels have been associated with metabolic syndrome, obesity, diabetes, hypertension, and chronic renal failure. Although some believe uric acid is elevated as a result of these diseases, there is now evidence that uric acid may play a role in the pathogenesis of these diseases. It is also known that GLUT9 is expressed in articular cartilage and is a uric acid transporter, and thus it is possible that GLUT9 plays a role in gout, a disease of uric acid deposition in the joints. In addition, some studies have suggested that intake of fructose plays an important role in causing elevated serum uric acid levels, especially in diabetes and obesity. It is possible that GLUT9, which seems to be both a fructose and a uric acid transporter, plays an important role in these conditions associated with hyperuricemia. splice variants; uric acid; fructose THE FACILITATIVE GLUCOSE TRANSPORTERS (SLC2A) belong to the facilitated transporter super gene family known as the glucose transporters (GLUTs). These integral membrane proteins are responsible for the facilitated diffusion of glucose and other hexoses into cells. Fourteen GLUTs have been identified. These transporters share several sequence and structural similarities, such as 12 transmembrane helices and conserved amino acid residues (18). The GLUT family is subdivided into three classes on the basis of comparison of amino acid sequences (35). GLUT1-4 are in class 1, GLUT5, -7, -9, and -11 are in class 2, and the last class consists of GLUT6, -8, -10, and -12 and the H ϩ /myoinositol transporter (35). GLUT14 is 95% identical to GLUT3 and thought to be a duplication of this class 1 transporter (37). The various GLUTs differ in their affinity for substrates, tissue distribution, and hormonal regulation. For example, GLUT4 is a glucose transporter found in muscle and adipose tissue that localizes to the plasma membrane in response to insulin, whereas GLUT11 is found in heart and skeletal muscle and appears to have a higher affinity for fructose than for glucose (16).All members of the GLUT...

Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses

“…5) Effect of extracellular substances on SLC2A9-mediated urate efflux. We have demonstrated previously that both D-glucose and D-fructose, which have been shown to be high-affinity permeants for SLC2A9a (11), are not competitive inhibitors of urate uptake. However, both of these hexoses can accelerate urate efflux mediated by SLC2A9a when placed in the extracellular medium, suggesting that facilitated movement of both urate and hexoses is likely mediated by the same carrier (9).…”

Hormonal and Chemical Regulation of the Glut9 Transporter in Mice

“…In mouse liver, Glut9 is localized at the basolateral membrane of hepatocytes and is responsible for transporting urate into hepatocytes, where the enzyme uricase further metabolizes urate into allantoin for excretion (Hediger et al, 2005;So and Thorens, 2010). In mouse kidney, Glut9 is abundantly localized on both the apical and basolateral membrane of distal convoluted tubules and transports urate from filtrate into blood (Anzai et al, 2008;Doblado and Moley, 2009;So and Thorens, 2010). The role of Glut9 as a major regulator of urate homeostasis has been clearly demonstrated by studies using systemic and liver-specific Glut9 knockout (KO) mice (Preitner et al, 2009).…”

Gender differences in the association between hyperuricemia and diabetic kidney disease in community elderly patients

“…The URAT1 may influence the gender difference of urate reabsorption in proximal tubule and excretion of urinary albumin (Bobulescu & Moe, 2012;Scheven, Joosten, de Jong, Bakker, & Gansevoort, 2014). In addition, glucose transporter isoform GLU9 has been identified as another important uric acid transporter and can exchange urate for glucose or fructose (Doblado & Moley, 2009); whether there is gender difference in its influence of albuminuria needs further investigations. We also found that older diabetic women were more likely to have hypertension, dyslipidemia, albuminuria and higher levels of mean BMI than men in this study.…”