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Int. J. Mol. Sci. 2014, 15(5), 8004-8023; doi:10.3390/ijms15058004
Article

Characterization of Timed Changes in Hepatic Copper Concentrations, Methionine Metabolism, Gene Expression, and Global DNA Methylation in the Jackson Toxic Milk Mouse Model of Wilson Disease

1
, 2
, 3
, 4
, 5
, 6
, 7
, 2
, 1
 and 2,*
1 Department of Nutrition, University of California Davis, 3135 Meyer Hall, One Shields Avenue, Davis, CA 95616, USA 2 Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, 4150 V Street, Suite 3500, Sacramento, CA 95817, USA 3 Department of Pathology, UCLA/Harbor Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA 4 Department of Public Health Sciences, Division of Biostatistics, University of California Davis, One Shields Avenue, Med-Sci 1C, Davis, CA 95616, USA 5 Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, VA Medical Center R-151, 4101 Woolworth Avenue, Omaha, NE 68105, USA 6 Department of Medical Microbiology and Immunology, University of California Davis, One Shields Avenue, Tupper Hall, Davis, CA 95616, USA 7 Department of Medical Microbiology and Immunology Genome Center, and MIND Institute, University of California Davis, One Shields Avenue, Tupper Hall, Davis, CA 95616, USA
* Author to whom correspondence should be addressed.
Received: 26 February 2014 / Revised: 14 April 2014 / Accepted: 15 April 2014 / Published: 7 May 2014
(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)
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Abstract

Background: Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). Methods: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Results: Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Conclusion: Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.
Keywords: Wilson disease; copper; DNA; methylation; gene expression Wilson disease; copper; DNA; methylation; gene expression
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Le, A.; Shibata, N.M.; French, S.W.; Kim, K.; Kharbanda, K.K.; Islam, M.S.; LaSalle, J.M.; Halsted, C.H.; Keen, C.L.; Medici, V. Characterization of Timed Changes in Hepatic Copper Concentrations, Methionine Metabolism, Gene Expression, and Global DNA Methylation in the Jackson Toxic Milk Mouse Model of Wilson Disease. Int. J. Mol. Sci. 2014, 15, 8004-8023.

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