File:PMC5404803 pgpm-10-129Fig3.png

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Author:MC Cleophas, LA Joosten, LK Stamp, N Dalbeth, OM Woodward, and Tony R Merriman,Department of Internal Medicine,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Department of Medicine, University of Otago Christchurch,Department of Medicine, University of Auckland, Department of Physiology, University of Maryland School of Medicine, Department of Biochemistry, University of Otago(Openi/National Library of Medicine) Source:https://openi.nlm.nih.gov/detailedresult?img=PMC5404803_pgpm-10-129Fig3&query=gout&it=xg&req=4&npos=17 Description:f3-pgpm-10-129: Schematic overview of the roles of ABCG2 in hyperuricemia and gout. (A) The ABCG2 transporter is highly expressed in the gut, where it regulates ATP-dependent uric acid excretion. The 141K ABCG2 variant leads to decreased surface expression, targeting of the misfolded protein to aggresomes and proteasomal degradation. In addition, the polymorphism increases miRNA-mediated degradation of mRNA. The resulting increase in circulating urate not only increases the risk of gout but can also induce a more pro-inflammatory state in monocytes due to epigenetic reprogramming.129 Colchicine and HDAC inhibitors (HDACi) can restore 141K surface expression and function. (B) Monosodium urate crystals can induce mitochondrial damage, leading to the release of mitochondrial reactive oxygen species and DNA (mtROS, mtDNA), which in turn can activate the NLRP3 inflammasome. This can be limited through autophagy-mediated clearance of damaged mitochondria. ABCG2 plays a role in this process. In defective or diminished autophagy, p62 can accumulate, bind to keap-1, and induce translocation of Nrf2 to the nucleus. Nrf2 induces transcription of heme oxygenase-1 and superoxide dismutase (HO-1, SOD), which can also induce NLRP3 inflammasome activation.Abbreviations: MSU, monosodium urate; HDACi, histone deacetylase inhibitors; TLR, Toll-like receptor; NLRP3, NBD, leucine-rich family [NLR], pyrin containing 3; ABCG2, ATP-binding cassette G2; IL, interleukin.