Page 13 - Copper-associated hepatitis in the Labrador retriever diagnosis, treatment and genetics

Introduction
The trace element copper plays an essential role in a variety of biological processes including mitochondrial respiration, antioxidant defense, neurotransmitter synthesis, connective tissue formation, pigmentation and iron metabolism. However, it is extremely toxic when present in excessive amounts. Therefore, copper concentrations in the body are tightly regulated1. The importance of proper functioning of its homeostatic regulation is illustrated by the genetic disorders Menkes disease (OMIM #309400) and Wilson disease (OMIM #277900), that result from mutations in genes coding for the homologous copper- transporting P-type ATPases ATP7A and ATP7B, respectively.
Dietary copper uptake takes place in the small intestine2, where CTR13 and possibly CTR24 and DMT15 can facilitate copper uptake into enterocytes. Copper is transported from the enterocytes into the portal circulation by ATP7A that is located at the basal membrane of the enterocyte under high copper conditions6. In the blood, copper is bound to small molecules such as histidine, and to serum proteins like α2-macroglobulin and albumin7 for transport to the liver, the primary site of copper storage8-10.
Copper enters the hepatocytes via CTR111 and is sequestered by small molecules like metallothionein12 and glutathione13 in the cytosol. Specialized copper chaperones shuttle copper to their destination molecules. CCS shuttles copper to SOD1, which participates in oxidative stress defense14. COX17 is the copper chaperone for the cytochrome C oxidase, which resides in the mitochondrial inner membrane and plays a critical role in the electron transport chain for cellular respiration15.
The copper chaperone ATOX116 delivers copper to ATP7B that is located in the trans Golgi compartment17-19. Here, copper is necessary for the formation of holo-ceruloplasmin, which is subsequently secreted into the blood20. In addition, ATP7B facilitates the excretion of excess copper into the bile21 (Figure 1). Mutations in ATP7B can result in Wilson disease ( WD), an autosomal recessive disorder22;23 characterized by copper accumulation in the liver, brain and cornea24. Clinical signs manifest in the form of hepatic, neurologic or psychiatric impairment and often become evident in people in the 2nd or 3rd decades of
General introduction
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Chapter 1