title: High copper selectively alters lipid metabolism and cell cycle machinery in the mouse model of Wilson disease.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Huster
authors.forename: Tina D
authors.initials: TD
authors.lastname: Purnat
authors.forename: Jason L
authors.initials: JL
authors.lastname: Burkhead
authors.forename: Martina
authors.initials: M
authors.lastname: Ralle
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Franziska
authors.initials: F
authors.lastname: Stuckert
authors.forename: N Erik
authors.initials: NE
authors.lastname: Olson
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lutsenko
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D002453:Cell Cycle; D015243:Cholesterol, VLDL / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005260:Female; D006527:Hepatolenticular Degeneration / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D015243:Cholesterol, VLDL; D002843:Chromatin; D051782:Sterol Regulatory Element Binding Protein 2; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases