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Hepatic Copper Transport

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Summary

Copper is an essential nutrient that is required in a number of critical metabolic path ways. This metal is absorbed in the stomach and duodenum, stored in the liver and excreted in the bile. The liver functions to maintain copper balance as the amount of copper excreted in the bile is directly proportional to the size of the hepatic copper pool. Biliary copper excretion increases rapidly as the hepatic copper pool expands, providing a mechanism that normally prevents systemic copper overload. However, as the biliary system provides the only route for copper excretion, any interference with this process, as may occur in cholestasis, will result in hepatic copper accumulation. The molecular mechanisms of biliary copper excretion have begun to be elucidated with identification of the genetic defect in Wilson disease, an inherited disorder resulting in hepatic copper accumulation. The Wilson disease gene encodes a copper-transporting P-type ATPase (ATP7B) localized to the trans-Golgi network of hepatocytes and required for biliary copper excretion. In this chapter we discuss what is currently known about the molecular basis of hepatic copper transport and overview the molecular pathogenesis of hepatic copper accumulation in Wilson disease and the cholestatic syndromes.

Introduction

A diverse but limited number of cuproproteins including cytochrome oxidase, ceruloplasmin, tyrosinase, dopamine β-hydroxylase, superoxide dismuatse, peptidyl β-amidating monoxygenase and lysl oxidase utilize copper as a cofactor in essential electron transfer reactions. 1 The signs and symptoms of copper deficiency result from the loss of activity of these copper-dependent enzymes and include impairment in cellular respiration, iron oxidation, pigment formation, neurotransmitter biosynthesis, antioxidant defense, peptide amidation, and connective tissue formation. The chemical reactivity that makes copper a useful cofactor in these metabolic pathways can also result in considerable cellular injury in those circumstances where the metabolism of this metal is disturbed.2 Therefore, unique cellular mechanisms have evolved that permit the intracellular trafficking and compartmentalization of copper, ensuring an adequate tissue supply of this metal and avoiding cellular toxicity.

Numerous food sources are rich in dietary copper and about half of the total daily intake of copper is absorbed, predominately in the stomach and duodenum. Biliary excretion serves as the only route for copper elimination and as there is no enterohepatic circulation of this metal, each day an amount of copper equivalent to that absorbed is excreted via the biliary tract (Fig. 1). Therefore, this pathway of absorption and excretion, which is the only physiologically relevant mechanism for maintaining copper homeostasis, is critically dependent upon normal liver function.3

Figure 1. Physiology of human copper metabolism.

Figure 1

Physiology of human copper metabolism. The liver is the central organ of copper homeostasis. Copper balance is determined by biliary excretion which is the only physiologic mechanism of excretion. There is no enterohepatic circulation of copper. (Modified (more...)

Copper is transported in the blood complexed to amino acids such as histidine and thus renal filtration from the plasma can also provide a mechanism for copper excretion, but only under circumstances of marked copper overload where tubular reabsorption is overwhelmed.

Hepatic Copper Metabolism

Overview

As noted in Fig. 1, the liver plays a critical role in copper metabolism, serving as both the central site of storage for this metal as well as the primary determinant regulating biliary excretion. Tracer kinetic studies utilizing copper isotopes reveal rapid hepatic clearance of this metal from the portal circulation. Approximately 24 hours following a single dose of radioactive copper, 10% of the isotope will reappear in the serum bound to the plasma protein ceruloplasmin. 4 This protein is a ferroxidase containing 95% of the copper present in plasma. Despite the abundance of copper in this protein, ceruloplasmin has no essential role in copper transport or distribution.4 The remaining copper present in the plasma is bound to amino acids and it is believed that these complexes provide the mechanism for transport of this metal to various tissues.

In the liver, hepatocytes are responsible for the uptake and storage of copper, as well as the regulation of excretion of this metal into the bile. The critical role of these cells in systemic copper homeostasis is illustrated by the normalization of copper metabolism in the severely copper-overloaded patient with Wilson disease following hepatic transplantation.5 Any increase in copper intake results in a similar increase in the hepatocyte copper pool and metabolic studies reveal that under normal conditions the amount of copper excreted in the bile will be directly proportional to the size of this pool.6 Given this capability to rapidly increase biliary copper excretion, hepatic copper excess is an unusual finding under normal physiological conditions. The form of copper appearing in the bile is unknown; however, several studies suggest that, once excreted into the bile, copper exists as an unabsorbable complex that is then eliminated in the stool. Although trace amounts of most plasma proteins are detected in bile, ceruloplasmin is not required for biliary copper excretion as patients with aceruloplasminemia reveal no evidence of impaired hepatic copper metabolism.4 Similarly, the lack of detectable ceruloplasmin in bile samples from patients with Wilson disease (vide infra) is simply a conse quence of the decreased serum concentration of this protein in affected patients and does not indicate a role for ceruloplasmin in the pathogenesis of this disease.

The human fetus acquires copper by placental transport. Biliary excretion is markedly decreased in the fetus and reaches adult capacity only after the first postnatal year.7 Consistent with this developmental physiology, copper accumulates in the fetal liver such that the hepatic copper content at birth is relatively increased. This stored hepatic copper only becomes available to the secretory pathway of the hepatocyte once bile flow increases after birth. As a result, the fetal and newborn liver synthesizes and secretes ceruloplasmin devoid of copper. The slow increase in postnatal biliary copper excretion is paralleled by an increase in the serum ceruloplasmin concentration, reflecting copper movement into the secretory pathway of the hepatocyte with resulting maturation in the capacity for holoceruloplasmin biosynthesis.4,8 The diminished serum ceruloplasmin content of newborn plasma abrogates the use of this protein as a marker for newborn screening in patients with Wilson disease or aceruloplasminemia.

Metallothionein

Metallothioneins are cysteine-rich, cytosolic proteins capable of binding several metal ions, including copper, under physiologic conditions.9 Although the human genome contains at least sixteen distinct genes encoding metallothioneins all clustered on chromosome 16, there are currently four well-characterized, highly homologous metallothioneins that have been extensively studied in mice and man. Two of these proteins, MT I and MT II, are ubiquitously expressed in all cell types including hepatocytes. While genetic experiments in mice suggest no essential role for MT I or MT II in copper metabolism, such studies do reveal a critical role for these proteins when the homeostasis of this metal is perturbed.1012 These findings indicate that these proteins protect against the toxicity of copper, presumably by binding and sequestration, and suggest the possibility of an essential role for metallothioneins in situations of hepatic copper excess.

Ctr1

Genetic studies in Saccharomyces cerevisiae identified a protein, termed ctr1, required for high-affinity copper uptake.13 Complementation experiments in ctr1Δ yeast resulted in characterization of a functional human homologue termed hCtr1.14 Genetic ablation of ctr1 function in mice causes early fetal demise revealing an essential role for this protein in embryonic development and suggesting a critical role for ctr1 in mammalian copper homeostasis.15,16 hCtr1 is a multimeric plasma membrane protein expressed in multiple cell types, which transports copper with high-affinity in a metal-specific and saturable manner dependent upon a series of critical methionine residues clustered in the extracellular domain.1719 These findings suggest that ctr1 functions as the high-affinity copper transporter at the basolateral surface of hepatocytes.

Ceruloplasmin

Ceruloplasmin is a multicopper oxidase that is required for the oxidation and movement of iron out of cells with mobilizable iron stores.4 In hepatocytes this protein is synthesized and secreted into the plasma following the incorporation of six atoms of copper in the secretory pathway. Any situation that prevents copper incorporation into ceruloplasmin will result in the secretion of an apoprotein that lacks enzymatic activity and is rapidly catabolized. In copper deficient states, as the size of the hepatocyte copper pool falls, the movement of copper into the secretory pathway decreases and biliary copper excretion and holoceruloplasmin secretion are diminished. As noted above, ceruloplasmin contains greater than 95% of the copper found in human plasma and therefore the serum concentration of this protein is a useful and sensitive marker of hepatic copper metabolism. In patients with Wilson disease, the lack of functional ATP7b activity (vide infra) abrogates copper transport into the hepatocyte secretory pathway, resulting in secretion of apoceruloplasmin and resulting in the decrease in serum ceruloplasmin concentration diagnostic of this disease. As revealed by earlier metabolic studies and more recent work in patients and mice with aceruloplasminemia, ceruloplasmin has no essential role in copper transport or metabolism.4

ATP7b

ATP7b is a copper-transporting P-type ATPase expressed within the secretory pathway of hepatocytes.20 This ATPase plays a critical role in copper homeostasis, as inherited loss-of-function mutations in the gene encoding human ATP7b result in the disorder of hepatic copper overload termed Wilson disease (vide infra). ATP7b is localized to the trans-Golgi network of hepatocytes and is required for the movement of copper into the secretory pathway for both incorporation into apoceruloplasmin and excretion into the bile.2023 With an increase in the hepatocyte cytosolic copper concentration, ATP7b localizes to a vesicular compartment near the canalicular membrane where copper is accumulated by this ATPase for subsequent excretion into the bile. As bile is the only route for copper excretion, this copper-dependent trafficking of ATP7b appears to provide a sensitive post-translational mechanism for maintaining copper homeostasis. The molecular mechanisms determining recycling of ATP7b have not been determined, but studies of an homologous copper-transporting ATPase, ATP7a, suggest that specific motifs within the carboxyl terminus may be required for this response.24,25 The mechanisms involved in subsequent copper movement across the canalicular membrane are also unknown.

ATP7b is a polytopic membrane protein with features characteristic of known P-type ATPases, including a consensus motif with an invariant aspartate reside (DKTGT) (Fig. 2).26 Phosphorylation of this aspartate residue results in a β-aspartyl phosphoryl intermediate that is required for ATP-dependent transfer of copper across the lipid bilayer. Recent experiments with ATP7b have demonstrated copper-dependent formation of this phosphorylated intermediate suggesting that the catalytic cycle of copper transport begins with the binding of copper to high affinity binding sites in the transmembrane channel, followed by ATP binding and transient aspartate phosphorylation.27 Site-directed mutagenesis studies suggest that the CPC sequence within the 6th transmembrane domain, highly conserved in all heavy metal transport P-type ATPases,28 is the site of copper binding during the catalytic cycle of transmembrane transport of this metal by ATP7b.20,29

Figure 2. Topological model of ATP7b.

Figure 2

Topological model of ATP7b. Specific amino acids are noted in the conserved motifs discussed in the text. The proposed mechanism of energy-dependent ATP-driven cation transport across the membrane is illustrated. (Modified and reproduced with permission (more...)

The amino terminus of ATP7b consists of six highly homologous domains, each of which contains the copper-binding motif MXCXXC (Fig. 2). These domains are critical for copper binding and transport and are the site of direct interaction with the copper chaperone atox1.3033 Structural analysis of an homologous domain in ATP7a reveals a linear bicoordinate copper-binding environment dependent upon the conserved cysteine residues in the MXCXXC motif.34 Recent studies suggest that this region interacts with the largest cytoplasmic loop of ATP7b, perhaps regulating copper transfer from these amino terminal domains to the CPC in the transport channel.35 The histidine residue in the sequence SEHPL located within this cytoplasmic loop is the site of the most common mutation (H1069Q) in Northern European populations with Wilson disease accounting for up to 40% of disease alleles. This mutation results in impaired trafficking of ATP7b indicating a role for this region in the intracellular localization.36

As noted above, upon increasing intracellular copper concentration, ATP7b traffics from the trans-Golgi network to a cytoplasmic location (Fig. 3). This vesicular compartment in mammalian cells into which copper is transported by ATP7b has not been well characterized. Copper transport into the homologous compartment in Saccharomyces cerevisiae is dependent upon the function of both the H+ transporting V-type ATPase37 and the CLC chloride channel Gef1.38,39 These proteins presumably provide the acidic milieu and the charge balance required to maintain active vectorial copper transport. Recent studies also indicate that the provision of fschloride ions by the CLC chloride channel in yeast is required for the allosteric assembly of copper into the ceruloplasmin homologue Fet3.40

Figure 3. Intracellular localization of the Wilson Disease copper-transporting ATPase (ATP7B).

Figure 3

Intracellular localization of the Wilson Disease copper-transporting ATPase (ATP7B). Primary rat hepatocytes were incubated for indicated times (A-C) in 50 μM copper or (D) 40 μM bathocuproine disulfonate (BCS) following copper incubation (more...)

Atox1

Under physiological circumstances intracellular copper availability is restricted by the presence of intracellular chelators.41 For this reason, copper delivery to specific pathways within the cell is mediated by a family of proteins termed copper chaperones.42 These metallochaperones function to provide copper directly to target proteins while protecting this metal from intracellular scavenging (Fig. 4). The copper chaperone atox1 is required for copper delivery to ATP7b in the secretory pathway and genetic disruption of the atox1 locus in mice reveals that this protein plays a critical role in perinatal copper homeostasis.43 Wilson disease-associated mutations in the amino terminus of ATP7b have been shown to result in a marked diminution in atox1 binding indicating that impaired copper delivery by this chaperone constitutes the molecular basis of Wilson disease in patients harboring these mutations.31 Atox1 contains a single copy of the MXCXXC copper-binding motif present in the amino-terminus of ATP7b and in vitro and in vivo studies indicate that these cysteines are required for copper binding and transport to this ATPase.30,31 The crystal structure of atox1 has been resolved and this structural data suggests a mechanism for copper transfer between atox1 and ATP7b dependent upon direct protein-protein interaction and copper binding at the MXCXXC motifs.44,45

Figure 4. Model of the proposed pathways of intracellular copper trafficking within the human hepatocyte.

Figure 4

Model of the proposed pathways of intracellular copper trafficking within the human hepatocyte. The copper chaperones, recycling of ATP7b and pathway of copper excretion into bile are illustrated. In this model, copper movement to the canalicular membrane (more...)

Murr1

The presence in Bedlington terriers of an inherited disorder of copper homeostasis prompted studies to map and identify the involved locus. These animals have impaired copper excretion into bile but no abnormality in copper incorporation into ceruloplasmin suggesting that the defect occurs distal to the function of ATP7b in intracellular copper transport (vide infra). This disorder has recently been shown to result from deletion of a gene on dog chromosome 10q26 encoding a small cytosolic protein termed murr1.46 The gene encoding murr1 is abundantly expressed in human liver suggesting that this protein plays a role in hepatic copper transport and biliary copper excretion in man.

Hepatic Copper Disorders

Wilson Disease

Wilson disease is an autosomal recessive disorder of copper metabolism resulting in hepatic cirrhosis and neurodegeneration. Recognition of this genetic disorder of hepatic copper homeostasis indicated that specific mechanisms are involved in copper trafficking within hepato- cytes, a concept confirmed with the cloning of the Wilson disease gene, (ATP7b).47 Loss of function of ATP7b in the hepatocyte results in a marked decrease in both holoceruloplasmin biosynthesis and biliary copper excretion with intracellular copper accumulation and eventual copper overload in most tissues (Fig. 4). Although ATP7b is expressed in extrahepatic tissues, the multi-organ copper overload observed in this disease is the result of impaired ATPase function in the hepatocyte, as this is reversed following hepatic transplantation.5,47 More than two hundred distinct mutations have been identified in affected patients, approximately 50% of which are missense, most within well-defined consensus motifs or predicted transmembrane domains.47,48 Biochemical analysis of these mutations has revealed specific molecular mechanisms accounting for Wilson disease including abnormalities in chaperone interaction, copper transport, subcellular localization and copper-induced trafficking of ATP7b.20,29,31,49,50

The model of cellular pathogenesis revealed by analysis of ATP7b mutations also provides a starting point for defining additional genetic and environmental factors affecting hepatic copper metabolism that may contribute to the clinical heterogeneity observed in individuals with Wilson disease. Such factors include proteins determining the rate of copper-delivery to the secretory pathway such as atox1, as well as potential homologues of the V-ATPase and gef1 chloride channel shown to be required for vesicular copper accumulation in yeast.3740 Metallothioneins are essential when copper homeostasis is perturbed12 and allelic variability or loss-of-function of these proteins might also contribute to clinical outcome in any given patient. Although little is known about the specific mechanisms resulting in hepatocyte injury following copper accumulation, recent studies implicating specific apoptotic pathways suggest additional proteins that may influence disease outcome.51 Although heterozygous loss of function of ATP7b is not associated with clinical abnormalities, the presence of such mutations might serve as risk factors promoting copper-mediated injury in more common liver disorders such as alcoholic cirrhosis.52

Animal models of Wilson disease have also provided insight into hepatic copper metabolism. Long Evans Cinnamon (LEC) rats have a marked impairment in biliary copper excretion with resulting hepatitis secondary to a deletion in the rat orthologue of ATP7b.53,54 Hepatic copper accumulation in these animals results in hepatocellular carcinoma and abnormalities in hepatic iron metabolism.55 As these findings are not observed in humans with Wilson disease, the data suggest significant species differences in the response of hepatocytes to copper accumulation. Toxic milk mice contain spontaneous missense mutations (M1356V or (G712D) in the murine orthologue of ATP7b.56,57 Newborn mice suckled by the affected mother develop severe copper deficiency indicating a critical role for this ATPase in perinatal copper metabolism. Interestingly, although adult mice demonstrate significant hepatic copper overload these animals do not develop cirrhosis again suggesting species specific differences in factors which determine the outcome of copper-mediated hepatocyte injury. Consistent with this concept, deletion of a portion of the murine ATP7b gene by homologous recombination also results in mice with significant hepatic copper-overload by 8 weeks of age but no evidence of hepatic cirrhosis.58

Although Wilson disease is the most common disorder resulting in hepatic copper overload, any process that interferes with biliary excretion will eventually result in hepatic copper accumulation.59 Accordingly, hepatic copper content is frequently elevated in cholestatic syndromes secondary to intrahepatic and extrahepatic bile duct injury.60 In such cases, the serum ceruloplasmin will be normal or elevated indicating that the defect in copper excretion is distal to the function of ATP7b in this pathway (Fig. 4). Although accumulated copper may play a role in the eventual hepatic injury observed in these conditions, this does not appear to be a major factor in such injury as chelation with D-penicillamine is not effective in reversing this process.60

Idiopathic Childhood Cirrhosis

A severe form of rapidly progressive cirrhosis associated with a marked increase in hepatic copper has been described in children from rural, middle class Hindu families in India.61 Originally termed Indian childhood cirrhosis, similar clinical cases have now been reported worldwide and this disorder is now referred to as idiopathic childhood cirrhosis.62 Affected children are diagnosed by two years of age with hepatosplenomegaly, elevation of serum aminotransferases, cirrhosis and elevated liver copper. Interestingly, the serum ceruloplasmin in these patients is normal or elevated, suggesting that the defect in biliary copper excretion is distal to the role of ATP7b in this process (Fig. 4). Epidemiological investigations of idiopathic childhood cirrhosis indicate that both genetic and environmental factors may play a role in this disease. These studies have revealed an increase in the copper content of the diet of affected children while analysis of some families suggests autosomal recessive inheritance with incomplete penetrance.63 In support of an underlying defect in hepatic copper excretion, D-penicillamine is effective in many cases and hepatic transplantation can be curative.

A similar form of copper-associated cirrhosis is observed as an autosomal recessive disorder in inbred Bedlington terriers.64 In these animals radioisotope studies reveal impaired biliary copper excretion but not holoceruloplasmin synthesis, once again suggesting a defect distal to the role of ATP7b in biliary copper excretion (Fig. 4). As noted above, genetic analysis has now localized the affected gene in these dogs and this should permit a more careful molecular analysis in affected patients. North Ronaldsay sheep also accumulate significant amounts of hepatic copper with concomitant liver injury suggesting that these animal models may allow for a detailed evaluation of the molecular mechanisms of canalicular bile excretion in children with idiopathic copper toxicosis.65

Acknowledgments

Work from the author's laboratory reported in this chapter was supported in part by National Institute of Health Grants DK44464, DK61763, and HD39952. Jonathan D. Gitlin is a recipient of a Burroughs-Welcome Scholar Award in Experimental Therapeutics.

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