Show simple item record

dc.contributor.authorGray, Lawrence W.
dc.contributor.authorPeng, Fangyu
dc.contributor.authorMolloy, Shannon A.
dc.contributor.authorPendyala, Venkata S.
dc.contributor.authorMuchenditsi, Abigael
dc.contributor.authorMuzik, Otto
dc.contributor.authorLee, Jaekwon
dc.contributor.authorKaplan, Jack H.
dc.contributor.authorLutsenko, Svetlana
dc.date.accessioned2013-10-25T17:52:27Z
dc.date.available2013-10-25T17:52:27Z
dc.date.issued2012-06
dc.identifier.bibliographicCitationGray, L. W., F. Y. Peng, et al. (2012). "Urinary Copper Elevation in a Mouse Model of Wilson's Disease Is a Regulated Process to Specifically Decrease the Hepatic Copper Load." PLoS One 7(6). DOI: 10.1371/journal.pone.0038327en_US
dc.identifier.issn1932-6203
dc.identifier.other10.1371/journal.pone.0038327
dc.identifier.urihttp://hdl.handle.net/10027/10329
dc.description2012 Gray et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The original version is available through Public Library of Science at DOI: 10.1371/journal.pone.0038327 .en_US
dc.description.abstractBody copper homeostasis is regulated by the liver, which removes excess copper via bile. In Wilson’s disease (WD), this function is disrupted due to inactivation of the copper transporter ATP7B resulting in hepatic copper overload. High urinary copper is a diagnostic feature of WD linked to liver malfunction; the mechanism behind urinary copper elevation is not fully understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live Atp7b2/2 mice at different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption spectroscopy directly demonstrate an age-dependent decrease in the capacity of Atp7b2/2 livers to accumulate copper, concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is associated with the down-regulation of the copper-transporter Ctr1 in the liver and appearance of a 2 kDa Small Copper Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific Ctr12/2 knockouts, which have normal ATP7B function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis, partially purified SCC-Cu competes with free copper for uptake by Ctr1. Thus, hepatic down-regulation of Ctr1 allows switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of WD.en_US
dc.description.sponsorshipThis work was supported by the National Institutes of Health grants 5F31DK084730 to LWG, 5R01DK079209 to JL, and 5P01GM067166 to SL and JHK. The mass-spectrometry work was done at the Metal Ion Core (Oregon Health and Science University), supported by NIH instrumentation grant S10-RR025512en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.titleUrinary Copper Elevation in a Mouse Model of Wilson’s Disease Is a Regulated Process to Specifically Decrease the Hepatic Copper Loaden_US
dc.typeArticleen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record