TY - JOUR
T1 - Consequences of copper accumulation in the livers of the Atp7b -/- (Wilson disease gene) knockout mice
AU - Huster, Dominik
AU - Finegold, Milton J.
AU - Morgan, Clinton T.
AU - Burkhead, Jason L.
AU - Nixon, Randal
AU - Vanderwerf, Scott M.
AU - Gilliam, Conrad T.
AU - Lutsenko, Svetlana
N1 - Funding Information:
We thank Dr. Whittaker (Oregon Graduate Institute School of Science and Engineering) for help with atomic absorption experiments; Tina Purnat (Oregon Health & Science University) for assistance with manuscript preparation; Carry Brady (Oregon Health and Science University) for help with histology studies; Angela Major for morphological studies performed in a Core Laboratory (supported by the National Institutes of Health grant P30 DK 56338 ) and James Barrish for electron microscopy (both at Texas Children's Hospital); and Dr. Hans-Juergen Kuehn (University Leipzig, Leipzig, Germany) and Dr. Uta Merle (University Heidelberg, Heidelberg, Germany) for providing valuable help with the measurements of ceruloplasmin oxidase activity.
Funding Information:
Supported by the National Institutes of Health (grant 1 P01 GM 067166-01 to S.L. ) and the Deutsche Forschungsgemeinschaft (postdoctoral fellowship HU 932/1-1 to D.H. ).
PY - 2006/2
Y1 - 2006/2
N2 - Wilson disease is a severe genetic disorder associated with intracellular copper overload. The affected gene, ATP7B, has been identified, but the molecular events leading to Wilson disease remain poorly understood. Here, we demonstrate that genetically engineered Atp7b-/- mice represent a valuable model for dissecting the disease mechanisms. These mice, like Wilson disease patients, have intracellular copper accumulation, low-serum oxidase activity, and increased copper excretion in urine. Their liver pathology developed in stages and was determined by the time of exposure to elevated copper rather than copper concentration per se. The disease progressed from mild necrosis and inflammation to extreme hepatocellular injury, nodular regeneration, and bile duct proliferation. Remarkably, all animals older than 9 months showed regeneration of large portions of the liver accompanied by the localized occurrence of cholangiocarcinoma arising from the proliferating bile ducts. The biochemical characterization of Atp7b-/- livers revealed copper accumulation in several cell compartments, particularly in the cytosol and nuclei. The increase in nuclear copper is accompanied by marked enlargement of the nuclei and enhanced DNA synthesis, with these changes occurring before pathology development. Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation.
AB - Wilson disease is a severe genetic disorder associated with intracellular copper overload. The affected gene, ATP7B, has been identified, but the molecular events leading to Wilson disease remain poorly understood. Here, we demonstrate that genetically engineered Atp7b-/- mice represent a valuable model for dissecting the disease mechanisms. These mice, like Wilson disease patients, have intracellular copper accumulation, low-serum oxidase activity, and increased copper excretion in urine. Their liver pathology developed in stages and was determined by the time of exposure to elevated copper rather than copper concentration per se. The disease progressed from mild necrosis and inflammation to extreme hepatocellular injury, nodular regeneration, and bile duct proliferation. Remarkably, all animals older than 9 months showed regeneration of large portions of the liver accompanied by the localized occurrence of cholangiocarcinoma arising from the proliferating bile ducts. The biochemical characterization of Atp7b-/- livers revealed copper accumulation in several cell compartments, particularly in the cytosol and nuclei. The increase in nuclear copper is accompanied by marked enlargement of the nuclei and enhanced DNA synthesis, with these changes occurring before pathology development. Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation.
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U2 - 10.2353/ajpath.2006.050312
DO - 10.2353/ajpath.2006.050312
M3 - Article
C2 - 16436657
AN - SCOPUS:33144475451
VL - 168
SP - 423
EP - 434
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 2
ER -