Wilson disease: not just a copper disorder. Analysis of a Wilson disease model demonstrates the link between copper and lipid metabolism

Abstract

Copper is an essential nutrient required for normal growth and development in many organisms. In humans, the disruption of normal copper absorption and excretion is associated with two severe disorders, known as Menkes disease and Wilson disease, respectively. The consequences of insufficient copper supply that is characteristic of Menkes disease have been largely linked to the inactivation of key metabolic enzymes, although other non-enzymatic processes may also be involved. In contrast, the consequences of copper accumulation in Wilson disease have been generally ascribed to copper-induced radical-mediated damage. Recent studies suggest that the cellular response to copper overload, particularly at the early stages of copper accumulation, involves more specific mechanisms and specific pathways. Genetic and metabolic characterization of animal models of Wilson disease has provided new insights into the pre-symptomatic effects of copper that is accumulated in the liver. The studies have uncovered unexpected links between copper metabolism, cell-cycle machinery, and cholesterol biosynthesis. We discuss these new findings along with the earlier reports on dietary effects of copper. Together these experiments suggest a tight link between lipid and copper metabolism and identify several candidate proteins that may mediate the cross-talk between copper status and lipid metabolism.

The Role of Copper as a Modifier of Lipid Metabolism

“…The analysis of liver transcriptome revealed that copper accumulation is associated with distinct metabolic changes: upregulation of genes involved in cell cycle and chromosome maintenance and down-regulation of lipid metabolism, especially cholesterol biosynthesis (78,79). The mRNA studies were complemented by the analysis of metabolites, which confirmed significant (30-40%) decrease of cholesterol in the liver, and the lower levels of VLDL cholesterol in the serum (79).…”

Copper in diseases and treatments, and copper‐based anticancer strategies

“…[64][65][66][67][68][69] Disruptions to normal copper homeostasis are evident in three human genetic disorders: MD, [70][71][72] occipital horn syndrome (OHS), 73,74 and WD. [75][76][77][78] Each disease results from the absence or dysfunction of homologous coppertransporting ATPases. The responsible gene for MD and OHS is the ATP7A gene, [79][80][81][82] whereas the ATP7B gene is responsible for WD.…”

In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

“…This same redox activity also poses a potential danger, requiring highly orchestrated regulation of copper pools to prevent oxidative stress and free radical damage events that are detrimental to health (12)(13)(14)(15)(16)(17)(18). Indeed, genetic disorders that disrupt copper homeostasis lead to severe and lethal conditions such as Menkes and Wilson's diseases (13,19,20), and imbalances in physiological copper levels and tissue miscompartmentalization arising from genetic and/or dietary factors are correlated with cancer, neurodegenerative diseases, and metabolic disorders such as obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”