부산대학교 도서관

R5362 --> 731.4 --> Epidemiological and observational studies have found a strong correlation between hyperuricemia (clinically elevated serum urate levels) and the onset of metabolic and systemic diseases. To investigate a potential causal role for urate in metabolic disease, we created a humanized mouse model utilizing a loss of function mutation in a critical intestinal urate transport protein, ABCG2. Male animals from this model were hyperuricemic and displayed fat deposition in the liver and significantly elevated serum glucose and insulin levels, hallmarks of metabolic dysfunction, and similar to what is often observed in high fructose diet models of NAFLD (Nonalcoholic fatty liver disease). However, the relationship between hyperuricemia, liver pathogenesis, and altered intestinal fructose uptake is largely unexplored. Using the Q140K+/+ hyperuricemia model we observed higher gene expression of Slc2a5 as well as increased abundance of its protein product, the apical fructose transporter GLUT5, in enterocytes. In addition, ex‐vivo intestinal fructose transport studies revealed a corresponding significant increase of fructose transport across the intestinal tissue of Q140K+/+ mice (16.497 ±5.955 vs. 34.684 ±5.31 µM/cm2). We hypothesized that HNF4a, the critical transcription factor that regulates the expression of many gut transport proteins, and has potential binding sites in the human and mouse Slc2a5 promoter region, might be sensitive to urate levels. Treatment of the human intestinal Caco‐2 cell monolayers with urate increased the protein abundance of both GLUT5 and HNF4a in a dose‐dependent manner, potentially explaining the observed increased mRNA levels of Slc2a5 in our model. We next explored the possibility that the GLUT5 abundance was further altered due to secondary urate effects on the critical transporter scaffold NEDD4 like E3 ubiquitin‐protein ligase (NEDD4L). Nedd4L gene expression was decreased, and its negative regulator, Sgk2, was significantly increased in intestinal tissue from the hyperuricemic model. Follow‐up experiments demonstrated SGK2 protein abundance is increased in Caco‐2 cells by extracellular urate. Further experiments are needed to confirm if hyperuricemia induced up‐regulation of SGK2, and subsequent down‐regulation of NEDD4L would prevent GLUT5 ubiquitination and increase its residence and abundance at the apical membrane. In conclusion, we find that hyperuricemia induced via common variants in the key intestinal urate transporter, ABCG2, can cause NAFLD and metabolic phenotypes indistinguishable from high fructose diet models of NAFLD. Here we demonstrate that urate may significantly upregulate the capacity for fructose reabsorption through the upregulation of Slc2a5 transcription and GLUT5 abundance, a finding that suggests human carriers of ABCG2 variants are not only at higher risk for hyperuricemia and gout but also the development of metabolic syndrome. [ABSTRACT FROM AUTHOR]