Hemin and iron increase synthesis and trigger export of xanthine oxidoreductase from hepatocytes to the circulation

DeVallance, Evan R.; Schmidt, Heidi M.; Seman, Madison; Lewis, Sara E.; Wood, Katherine C.; Vickers, Schuyler D.; Hahn, Scott A.; Velayutham, Murugesan; Hileman, Emily A.; Vitturi, Dario A.; Leonardi, Roberta; Straub, Adam C.; Kelley, Eric E.

doi:10.1016/j.redox.2023.102866

Cited by 5 publications

(2 citation statements)

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“…Additionally, the KRTCAP2 gene may influence the production and clearance of uric acid by modifying the expression as well as the function of the enzyme xanthine oxidoreductase (XOR), thereby impacting uric acid production and clearance [ 37 ]. KRTCAP2 may regulate the expression of the xanthine oxidoreductase (XOR) gene by modulating key transcription factors, such as Sp1 or PPARγ [ 38 , 39 ]. For instance, Sp1 could enhance the activity of the XOR promoter, thereby increasing XOR expression, while changes in KRTCAP2 expression could influence Sp1 activity, thereby indirectly regulating uric acid production.…”

Section: Discussionmentioning

confidence: 99%

Single-cell and genome-wide Mendelian randomization identifies causative genes for gout

Yang,

Hu,

Zhang

et al. 2024

Arthritis Res Ther

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Background Gout is a prevalent manifestation of metabolic osteoarthritis induced by elevated blood uric acid levels. The purpose of this study was to investigate the mechanisms of gene expression regulation in gout disease and elucidate its pathogenesis. Methods The study integrated gout genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data for analysis, and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and gout. Results We identified 17 association signals for gout at unique genetic loci, including four genes related by protein-protein interaction network (PPI) analysis: TRIM46, THBS3, MTX1, and KRTCAP2. Additionally, we discerned 22 methylation sites in relation to gout. The study also found that genes such as TRIM46, MAP3K11, KRTCAP2, and TM7SF2 could potentially elevate the risk of gout. Through a Mendelian randomization (MR) analysis, we identified three proteins causally associated with gout: ADH1B, BMP1, and HIST1H3A. Conclusion According to our findings, gout is linked with the expression and function of particular genes and proteins. These genes and proteins have the potential to function as novel diagnostic and therapeutic targets for gout. These discoveries shed new light on the pathological mechanisms of gout and clear the way for future research on this condition.

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Section: Discussionmentioning

confidence: 99%

Single-cell and genome-wide Mendelian randomization identifies causative genes for gout

Yang,

Hu,

Zhang

et al. 2024

Arthritis Res Ther

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show abstract

“…3 ). During reperfusion, a burst of ROS from the mitochondrial respiratory chain and NOX1 aggravates IRI ( Hebbel et al, 2020 ).The conversion of xanthine dehydrogenase to xanthine oxidase (XO) generates superoxide and hydroxyl radicals, contributing to ROS formation ( MacKinney et al, 2019 , DeVallance et al, 2023 ). XO-mediated degradation of oxyhemoglobin releases hemin and iron, triggering additional ROS formation ( Schmidt et al, 2021 , Schmidt et al, 2023 ).…”

Section: Ferroptosis – Vaso-occlusion and Hemolysis In Scdmentioning

confidence: 99%