Solute carrier family 2 member 9 (SLC2A9) is a voltage-driven transporter that mediates cellular uptake and efflux of various substrates such as uric acid. Here, we investigate the role of E4 promoter-binding protein 4 (E4BP4), a transcription factor, in regulating hepatic SLC2A9 in mice. Effects of E4BP4 on hepatic SLC2A9 and other transporters were examined using E4bp4 knockout (E4bp4 -/-) mice. Transporting activity of SLC2A9 was assessed using uric acid as a prototypical substrate. We found that three SLC genes (i.e., Slc2a9, Slc17a1, and Slc22a7) were upregulated in the liver in E4bp4-/- mice with Slc2a9 altered the most. E4bp4 ablation in mice dampened the daily rhythm in hepatic SLC2A9, in addition to increasing its expression. Furthermore, E4bp4-/- mice showed increased hepatic uric acid but reduced uric acid in the plasma and urine. Consistently, allantoin, a metabolite of uric acid generated in the liver, was increased in the liver of E4bp4-/- mice. E4bp4 ablation also protected mice from potassium oxonate-induced hyperuricemia. Moreover, negative effects of E4BP4 on SLC2A9 were validated in Hepa-1c1c7 and primary mouse hepatocytes. Additionally, according to luciferase reporter and chromatin immunoprecipitation assays, E4BP4 repressed Slc2a9 transcription and expression via direct binding to a D-box (-531 bp to -524 bp) in the P2 promoter. In conclusion, E4BP4 was identified as a novel regulator of SLC2A9 and uric acid homeostasis, which might facilitate new therapies for reducing uric acid in various conditions related to hyperuricemia. SIGNIFICANCE STATEMENT: Our findings identify E4BP4 as a novel regulator of SLC2A9 and uric acid homeostasis, which might facilitate new therapies for reducing uric acid in various conditions related to hyperuricemia.
Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.