Regulation of heme synthesis and proteasomal activity by copper: Possible implications for Wilson's disease

The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 01/2009; 28(3):209-21. DOI: 10.1615/JEnvironPatholToxicolOncol.v28.i3.20
Source: PubMed


Wilson's disease (Wd) is a genetic disorder resulting in Cu2+ accumulation, and is caused by mutations in the ATP7B gene, the copper transporter. In vivo studies show a correlation between Cu2+ accumulation and malfunction of the heme biosynthesis pathway. In this study, we describe multiple effects of Cu2+ accumulation on heme synthesis, which, in turn, affect proteasomal activity. Cu2+ toxicity was examined in two hepatocellular carcinoma cell lines, HepG2 and Hep3B, with Hep3B cells containing an integrated hepatitis B virus genome. Exposure of HepG2 and Hep3B cells to Cu2+ inhibited the enzymes PBGD and ALAD of the heme synthesis pathway and, in parallel, upregulated heme oxygenase-1 (HO-1). Proto-porphyrin IX (PpIX) and the heme pool were reduced as a result of these processes. PpIX synthesis was found to be lower in cells expressing the mutant ATP7B (P1134P), compared to those expressing the WT enzyme. Proteasomal activity was inhibited under Cu2+ treatment in HepG2 cells; however, Cu2+ induced marked proteosomal acceleration in Hep3B cells. Under these conditions, Ub-conjugated proteins were gradually accumulated, whereas treatment with bathocuproine disulfonic acid (BCS), a Cu2+ chelator, reversed this effect. In conclusion, our data suggest that copper downregulates the heme synthesis pathway in hepatocellular cells and further reduces it in the presence of mutated ATP7B.

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    • "Additional local or systemic copper dependent pathways may also affect iron absorption. We hypothesized that changes in either systemic or intestinal copper status regulate HIF-2α and as consequence iron absorption genes since: (i) we and others have shown that Cybrd1, Slc11a2 and Slc40a1 are bona fide Hif-2α targets [6], [7]; (ii) in vitro evidence suggests that changes in cellular copper levels regulate HIF-1α [20] and (iii) anemia associated with genetic disorders of copper metabolism could lead to increases in tissue hypoxia and stabilize HIF-2α [21]–[25]. We demonstrate in a mouse model of nutritional copper deficiency an increase in duodenal hypoxia and Hif-2α; i.p. copper injection alleviated copper deficiency anemia, reduced tissue hypoxia and modulated HIF-2α and iron absorption genes (Slc40a1, Slc11a2, and Cybrd1) independently of intestinal iron levels or liver hepcidin. "
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    PLoS ONE 03/2013; 8(3):e59538. DOI:10.1371/journal.pone.0059538 · 3.23 Impact Factor
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    Journal of Fluorescence 11/2010; 21(2):835-9. DOI:10.1007/s10895-010-0773-3 · 1.93 Impact Factor