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Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified  COMMD1  as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of  Commd1  deficiency on hepatic copper metabolism in mice. Liver-specific  Commd1  knockout mice ( Commd1   Δhep ) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in  Commd1   Δhep  mice by biochemical and histological analyses, and compared to wild-type littermates.  Commd1   Δhep  mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly,  Commd1   Δhep  mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in  Commd1   Δhep  mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in  Commd1   Δhep  mice could be detected. Despite the absence of hepatocellular toxicity in  Commd1   Δhep  mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis.

Liver-Specific Commd1 Knockout Mice Are Susceptible to Hepatic Copper Accumulation