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J. Biol. Chem., Vol. 282, Issue 11, 8343-8355, March 16, 2007

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High Copper Selectively Alters Lipid Metabolism and Cell Cycle Machinery in the Mouse Model of Wilson Disease^*

Dominik Huster¹², Tina D. Purnat¹, Jason L. Burkhead, Martina Ralle, Oliver Fiehn^¶, Franziska Stuckert, N. Erik Olson^||, Daniel Teupser^**, and Svetlana Lutsenko³

From the Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239, the Department of Medicine II and ^**Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University of Leipzig, 04103 Leipzig, Germany, ^¶University of California Davis Genome Center, Davis, California 95616, and ^||VizX Labs, Seattle, Washington 98119

Copper is essential for human physiology, but in excess it causes the severe metabolic disorder Wilson disease. Elevated copper is thought to induce pathological changes in tissues by stimulating the production of reactive oxygen species that damage multiple cell targets. To better understand the molecular basis of this disease, we performed genome-wide mRNA profiling as well as protein and metabolite analysis for Atp7b^-/- mice, an animal model of Wilson disease. We found that at the presymptomatic stages of the disease, copper-induced changes are inconsistent with widespread radical-mediated damage, which is likely due to the sequestration of cytosolic copper by metallothioneins that are markedly up-regulated in Atp7b^-/- livers. Instead, copper selectively up-regulates molecular machinery associated with the cell cycle and chromatin structure and down-regulates lipid metabolism, particularly cholesterol biosynthesis. Specific changes in the transcriptome are accompanied by distinct metabolic changes. Biochemical and mass spectroscopy measurements revealed a 3.6-fold decrease of very low density lipoprotein cholesterol in serum and a 33% decrease of liver cholesterol, indicative of a marked decrease in cholesterol biosynthesis. Consistent with low cholesterol levels, the amount of activated sterol regulatory-binding protein 2 (SREBP-2) is increased in Atp7b^-/- nuclei. However, the SREBP-2 target genes are dysregulated suggesting that elevated copper alters SREBP-2 function rather than its processing or re-localization. Thus, in Atp7b^-/- mice elevated copper affects specific cellular targets at the transcription and/or translation levels and has distinct effects on liver metabolic function, prior to appearance of histopathological changes. The identification of the network of specific copper-responsive targets facilitates further mechanistic analysis of human disorders of copper misbalance.

Received for publication, August 7, 2006 , and in revised form, January 4, 2007.

^* This work was supported in part by National Institutes of Health Grant PO1 GM 067166-01 (to S. L.) and Oregon Health & Science University Medical Research Foundation grant (to S. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables I-VI and Fig. 1.

¹ Both authors contributed equally to this work.

² Recipient of a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft Grant HU 932/1-1.

³ To whom correspondence should be addressed: Oregon Health & Science University, L224, Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-6953; Fax: 503-494-8393; E-mail: lutsenko{at}ohsu.edu.

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