**2. Gout and Hyperuricemia**

Hyperuricemia represents a prolonged pathophysiological increased serum urate concentration, often defined as >6.0 mg/dL (>360 µmol/L) for females and >7.0 mg/dL (>420 µmol/L) for males [1,18], which is either caused by an increased hepatic biosynthesis or a reduced renal or intestinal excretion of urate [19]. Under physiological conditions, urate is derived from the enzymatic degradation of purine nucleobases/nucleotides, which are involved in a multitude of biochemical processes, such as energy metabolism and the formation of RNA and DNA [20]. In humans, urate is the terminal metabolite of purine catabolism derived from purines that do not enter the salvage pathway for the resynthesis of ATP or GTP [19]. Therefore, secondary hyperuricemia can be induced by an excessive intake of purine-rich food (e.g., red meat, offal, seafood) [21], cellular degradation processes, and high cell turnover in the context of leukemia/lymphoma [22] or anticancer treatment with chemo- or radiation therapy [23], which all increase the availability of free purines. In addition to a diet high in purines, other lifestyle-related behaviors such as excessive intake of fructose [24,25] and alcohol abuse [26,27] can also trigger hyperuricemia, which explains the high prevalence in industrialized countries and the increasing prevalence in developing countries [28]. Aside from the aforementioned environmental factors, also genetic defects in enzymes responsible for the biotransformation of purine bases can favor primary hyperuricemia, as is the case in Lesch–Nyhan or Kelley–Seegmiller syndromes [29]. In line with this notion, the heritability of hyperuricemia is substantial, suggesting important genetic contributions to urate homeostasis [30]. In pharmacotherapy, uricostatic drugs like the xanthinoxidase inhibitor allopurinol can be used to normalize hyperuricemia by preventing the last step in urate biosynthesis. Under this treatment, intermediates of the purine metabolism such as inosine, hypoxanthine, and xanthine accumulate, yet exhibit a better water solubility and a lower tendency to form crystals than urate. Unlike secondary hyperuricemias that are triggered by increased urate biosynthesis, the vast number (>90%) of primary hyperuricemia cases result from a decreased ability of the kidney or intestine to excrete urate [31]. The majority of urate (roughly 70%) is eliminated by the kidney, where it is freely filtered by the glomerulus [32]. Urate homeostasis is primarily influenced by renal proximal tubule cells, which express several transporters that either reabsorb urate (e.g., URAT1 at the apical and GLUT9 at the basolateral membrane) [33–36] or are involved in urate excretion (e.g., NPT1/4 at the apical and OAT1/3 at the basolateral membrane) [20,35,37,38]. Indeed, uricosuric drugs such as the URAT1 inhibitors benzbromarone as well as probenecid and lesinurad are used in pharmacotherapy to treat hyperuricemia by inhibiting renal reabsorption of urate [39]. In addition to transporters of the salute carrier (SLC) and the organic anion transporter (OAT) protein families, ABC transporters such as ABCG2 and ABCC4 are also involved in urate excretion [32,37]. As the previously mentioned other transporters, ABCG2 was shown to be located in the apical brush border membrane of renal proximal tubule cell [40]. In the intestine, the major site for the remaining 30% of urate excretion, the mechanisms of urate excretion are less well defined [38]. Urate transporters GLUT9 [41] and in particular ABCG2 [42] are highly expressed in intestinal epithelial cells and may thus represent interesting new pharmacological targets for the treatment of hyperuricemia [43–47]. Nonetheless, with regard to the sites of urate excretion (kidney & intestine) and the complex interplay of transporter-mediated excretion and reabsorption of urate in the kidney, the mechanisms of urate homeostasis are still not fully understood. However, single nucleotide polymorphisms (SNPs) in different genes involved in urate transport have been associated with hyperuricemia [48], thereby emphasizing the multicausal complexity of gout pathology [49]. In this article, we aim to focus on ABCG2, which has been identified as an important urate transporter in the intestine and

the kidney [40,50–52], and discuss its role in renal and extra-renal urate excretion as well as in primary hyperuricemia and early-onset gout.
