Body copper homeostasis is regulated by the liver, which removes excess copper via bile. In Wilson’s disease (WD), this
function is disrupted due to inactivation of the copper transporter ATP7B resulting in hepatic copper overload. High urinary
copper is a diagnostic feature of WD linked to liver malfunction; the mechanism behind urinary copper elevation is not fully
understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live Atp7b2/2 mice at
different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that
urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption
spectroscopy directly demonstrate an age-dependent decrease in the capacity of Atp7b2/2 livers to accumulate copper,
concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell
necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is
associated with the down-regulation of the copper-transporter Ctr1 in the liver and appearance of a 2 kDa Small Copper
Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific Ctr12/2 knockouts, which have normal ATP7B
function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis,
partially purified SCC-Cu competes with free copper for uptake by Ctr1. Thus, hepatic down-regulation of Ctr1 allows
switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that
the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion
may contribute to an improved diagnosis and monitoring of WD