Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2

Abstract

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−/− 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−/− 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−/− mice, the enzymatic activity was higher in Hfe−/− 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−/− 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−/− 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.

Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice

“…Chronic exposure to excess iron leads to decreased p53 protein levels in cells. We have reported recently that p53 protein levels are significantly decreased in Hfe −/− mouse colon and that the phenomenon is associated with decreased transcriptional activity of this protein [43]. As p53 is either mutated or decreased in most cancers, including colon cancer, the decrease in p53 protein levels in colon in response to excessive iron/heme certainly contributes to the observed potentiation of colitis and colon cancer in Hfe −/− mice.…”

Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

“…Hemochromatosis is a genetic disorder arising from loss-of-function mutations in the iron-regulatory protein called HFE (High Fe or histocompatibility-like protein involved in Fe regulation). It is an iron-overload disease associated with increased levels of iron in circulation and a consequent increased uptake and accumulation of iron in most organs, including the liver, intestine, colon, and retina [52,53,88,102,103]. Interestingly, the iron levels in the duodenum and macrophages are lower than normal in this disorder.…”

Polycystic ovary syndrome and iron overload: biochemical link and underlying mechanisms with potential novel therapeutic avenues

“…The common clinical features include liver cirrhosis, liver cancer, diabetes, cardiomyopathy, nephropathy, arthritis, pituitary dysfunction, sexual dysfunction, and potential association with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Using a mouse model of hemochromatosis ( Hfe -null mice) which phenocopies the human disease, we demonstrated additional pathologic features in the disorder: visual dysfunction [ 51 ], colitis and colon cancer [ 52 ], gout [ 53 ], and diabetic nephropathy [ 54 ]. There seems to be some variability in the clinical spectrum depending on whether the disease is caused by C282Y mutation or H63D mutation.…”