{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T18:08:10Z","timestamp":1774634890471,"version":"3.50.1"},"reference-count":52,"publisher":"Portland Press Ltd.","issue":"8","license":[{"start":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T00:00:00Z","timestamp":1585785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,4,30]]},"abstract":"<jats:p>Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis\/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe\u2212\/\u2212 mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe\u2212\/\u2212 mice compared with controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe\u2212\/\u2212 mice, the enzymatic activity was higher in Hfe\u2212\/\u2212 mice. We then examined various transporters involved in UA absorption\/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe\u2212\/\u2212 mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe\u2212\/\u2212 mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron\/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis.<\/jats:p>","DOI":"10.1042\/bcj20190873","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T10:38:23Z","timestamp":1585823903000},"page":"1499-1513","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression\/activity of xanthine oxidase and ABCG2"],"prefix":"10.1042","volume":"477","author":[{"given":"Bojana","family":"Ristic","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sathish","family":"Sivaprakasam","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monisha","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0799-6018","authenticated-orcid":false,"given":"Vadivel","family":"Ganapathy","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2020,4,29]]},"reference":[{"key":"2021112218074383700_BCJ-2019-0873C1","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1172\/JCI42344","article-title":"Uric acid transport and disease","volume":"120","year":"2010","journal-title":"J. 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