High Copper Selectively Alters Lipid Metabolism and Cell Cycle Machinery in the Mouse Model of Wilson Disease
Dominik Huster, Tina D. Purnat, Jason L. Burkhead, Martina Ralle, Oliver Fiehn, Franziska Stuckert, N. Erik Olson, Daniel Teupser and Svetlana Lutsenko. J Biol Chem. 2007 Jan 7; [Epub ahead of print].
In a recent study published in the Journal
of Biological Chemistry, researchers from
Oregon Health & Science University used
IPA to elucidate the molecular and metabolic
changes that accompany the initial stages
of the metabolic disorder Wilson Disease (WD).
IPA analysis of copper-induced gene expression
changes in a mouse model of WD enabled molecular
characterization of the disease, and initial
steps toward the identification of markers
of disease progression.
To understand the molecular events associated
with the early stages of copper overload in
Wilson Disease, the research team measured
changes in the hepatic mRNAs in 6-week-old
Atp7b-/- mice (a mouse model of WD). IPA analysis
of copper-specific gene expression changes
revealed selective perturbation of the cell-cycle
machinery and lipid metabolism. Pathway analysis
also revealed that oxidative stress is unlikely
to be central to the early, pre-symptomatic
stages of the disease. Network analysis further
highlighted the impact of elevated copper
on SREBP-2 activity, and the subsequent impact
of SREBP-2 inhibition on its transcriptional
targets.
These studies provide mechanistic insight
into the initial stages of pathology induced
by copper overload in WD, and may pave the
way for detailed analysis of other copper-induced
pathologies. The approach outlined by the
OHSU team provides a viable strategy for identifying
molecular changes and cellular responses specific
to WD, which may eventually serve as useful
diagnostic tools.
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