Hostname: page-component-586b7cd67f-l7hp2 Total loading time: 0 Render date: 2024-11-21T14:59:38.416Z Has data issue: false hasContentIssue false
  • English
  • Français

Molecular regulation of copper excretion in the liver

Published online by Cambridge University Press:  07 March 2007

Cisca Wijmenga  and
Leo W. J. Klomp
Cisca Wijmenga*
Affiliation:
Department of Biomedical Genetics, University Medical Center, Stratenum 2.117, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Leo W. J. Klomp
Affiliation:
Department of Biomedical Genetics, University Medical Center, Stratenum 2.117, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
*
Corresponding author: Dr Cisca Wijmenga, fax + 31 30 253 8479, email t.n.wijmenga@med.uu.nl
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Cu is an essential nutrient that is required for a broad range of cellular and molecular processes. Mammals have efficient systems to control Cu homeostasis that operate at the level of controlling uptake, distribution, sequestration and excretion of Cu. The study of diseases associated with disturbed Cu homeostasis has greatly enhanced our understanding of the molecular mechanisms involved in Cu metabolism. In man the liver is responsible for excreting excess Cu from the body by means of biliary secretion. Wilson disease is a severe human disorder characterized by Cu accumulation in the liver as a result of a deficiency in biliary Cu secretion. This disorder is caused by mutations in the gene that encodes a Cu-transporting P-type ATPase (ATP7B). The MURR1 gene was identified recently, and it was hypothesized that this gene is also essential for biliary Cu excretion and is presumed to act downstream of ATP7B. MURR1 is mutated in canine Cu toxicosis, a disorder with phenotypic characteristics similar to those of Wilson disease. MURR1 encodes a protein that is of unknown function and is without detectable sequence homology to known proteins. MURR1 is readily detected in all tissues and cell types, suggesting that it may exhibit a pleiotropic function in different organs, which may or may not be exclusively linked to Cu homeostasis. The use of genetic, biochemical and genomic tools, as well as the development of appropriate models in organisms other than dog, will allow the elucidation of the molecular and cellular function of MURR1 in relation to hepatic Cu homeostasis and biliary Cu excretion.

Keywords

Copper metabolismBiliary excretionMURR1
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 1 , February 2004 , pp. 31 - 39
Copyright
Copyright © The Nutrition Society 2004

References

Askwith, C & Kaplan, J (1998) Iron and copper transport in yeast and its relevance to human disease. Trends in Biochemical Sciences 23, 135–138.CrossRefGoogle ScholarPubMed
Bochner, BR (2003) New technologies to assess genotype–phenotype relationships. Nature Reviews Genetics 4, 309–314.CrossRefGoogle ScholarPubMed
Brummelkamp, TR, Bernards, R & Agami, R, (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553.CrossRefGoogle ScholarPubMed
Bull, PC, Thomas, GR, Rommens, JM, Forbes, JR & Cox, DW, (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genetics 5, 327–337.CrossRefGoogle Scholar
Dagenais, SL, Guevara-Fujita, M, Loechel, R, Burgess, AC, Miller, DE, Yuzbasiyan-Gurkan, V, Brewer, GJ & Glover, TW, (1999) The canine copper toxicosis locus is not syntenic with ATP7B or ATX1 and maps to a region showing homology to human 2p21. Mammalian Genome 10, 753–756.Google ScholarPubMed
De Freitas, J, Wintz, H, Kim, JH, Poynton, H, Fox, T & Vulpe, C (2003) Yeast, a model organism for iron and copper metabolism studies. Biometals 16, 185–197.CrossRefGoogle Scholar
Duggan, DJ, Bittner, M, Chen, Y, Meltzer, P & Trent, JM (1999) Expression profiling using cDNA microarrays. Nature Genetics 21, Suppl., 10 – 14.CrossRefGoogle ScholarPubMed
Eisses, JF & Kaplan, JH (2002) Molecular characterization of hCTR1, the human copper uptake protein. Journal of Biological Chemistry 277, 29162–29171.CrossRefGoogle ScholarPubMed
Freimer, N & Sabatti, C (2003) The human phenome project. Nature Genetics 34, 15–21.CrossRefGoogle ScholarPubMed
Gross, C, Kelleher, M, Iyer, VR, Brown, PO & Winge, DR (2000) Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays. Journal of Biological Chemistry 275, 32310–32316.CrossRefGoogle ScholarPubMed
Gross, JB Jr, Myers, BM, Kost, LJ, Kuntz, SM & LaRusso, NF (1989) Biliary copper excretion by hepatocyte lysosomes in the rat: Major excretory pathway in experimental copper overload. Journal of Clinical Investigations 83, 30–39.CrossRefGoogle ScholarPubMed
Hamadeh, HK, Amin, RP, Paules, RS & Afshari, CA (2002) An overview of toxicogenomics. Current Issues in Molecular Biology 4, 45–56.Google ScholarPubMed
Hamza, I, Faisst, A, Prohaska, J, Chen, J, Gruss, P & Gitlin, JD (2001) The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proceedings of the National Academy of Sciences USA 98, 6848–6852.CrossRefGoogle Scholar
Hamza, I, Prohaska, J & Gitlin, JD (2003) Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase. Proceedings of the National Academy of Sciences USA 100, 1215–1220.CrossRefGoogle ScholarPubMed
Hamza, I, Schaefer, M, Klomp, LW & Gitlin, JD, (1999) Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis. Proceedings of the National Academy of Sciences USA 96, 13363–13368.CrossRefGoogle ScholarPubMed
Hardy, RM, Stevens, JB & Stowe, CM, (1975) Chronic progressive hepatitis in Bedlington terriers associated with elevated liver copper concentrations. Minnesota Veterinarian 15, 13–24.Google Scholar
Hung, IH, Suzuki, M, Yamaguchi, Y, Yuan, DS, Klausner, RD & Gitlin, JD (1997) Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae. Journal of Biological Chemistry 272, 21461–21466.CrossRefGoogle ScholarPubMed
Huster, D, Hoppert, M, Lutsenko, S, Zinke, J, Lehmann, C, Mossner, J, Berr, F & Caca, K (2003) Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines. Gastroenterology 124, 335–345.CrossRefGoogle ScholarPubMed
Ito, T, Tashiro, K, Muta, S, Ozawa, R, Chiba, T, Nishizawa, M, Yamamoto, K, Kuhara, S & Sakaki, Y, (2000) Toward a protein–protein interaction map of the budding yeast: A comprehensive system to examine two-hybrid interactions in all possible combinations between the yeast proteins. Proceedings of the National Academy of Sciences USA 97, 1143–1147.CrossRefGoogle Scholar
Kipp, H & Arias, IM (2002) Trafficking of canalicular ABC transporters in hepatocytes. Annual Review of Physiology 64, 595–608.CrossRefGoogle ScholarPubMed
Klomp, AE, Juijn, JA van der Gun, LT van den Berg, IE, Berger, R & Klomp, LW (2003a) The N-terminus of the human copper transporter 1 (hCTR1) is localized extracellularly, and interacts with itself. Biochemical Journal 370, 881–889.CrossRefGoogle Scholar
Klomp, AE, Tops, BB, Van Denberg, IE, Berger, R & Klomp, LW (2002) Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochemical Journal 364, 497–505.CrossRefGoogle ScholarPubMed
Klomp, AEM, Van de Sluis, B, Klomp, LWJ & Wijmenga, C (2003b) The ubiquitously expressed MURR1 protein is absent in canine copper toxicosis. Journal of Hepatology 39, 703–709.CrossRefGoogle ScholarPubMed
Klomp, LW, Lin, SJ, Yuan, DS, Klausner, RD, Culotta, VC & Gitlin, JD (1997) Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. Journal of Biological Chemistry 272, 9221–9226.CrossRefGoogle ScholarPubMed
Kuo, YM, Zhou, B, Cosco, D & Gitschier, J (2001) The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proceedings of the National Academy of Sciences USA 98, 6836–6841.CrossRefGoogle ScholarPubMed
Larin, D, Mekios, C, Das, K, Ross, B, Yang, AS & Gilliam, TC, (1999) Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone, HAH1p. Journal of Biological Chemistry 274, 28497–28504.CrossRefGoogle Scholar
Lee, J, Prohaska, JR & Thiele, DJ, (2001) Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proceedings of the National Academy of Sciences USA 98, 6842–6847.CrossRefGoogle ScholarPubMed
Linder, MC (2001) Copper and genomic stability in mammals. Mutation Research 475, 141–152.CrossRefGoogle ScholarPubMed
Muller, F, Blader, P & Strahle, U, (2002) Search for enhancers: teleost models in comparative genomic and transgenic analysis of cis regulatory elements. Bioessays 24, 564–572.CrossRefGoogle ScholarPubMed
Müller, M & Kersten, S (2003) Nutrigenomics: goals and strategies. Nature Reviews Genetics 4, 315–322.CrossRefGoogle ScholarPubMed
Müller, T, Feichtinger, H, Berger, H & Müller, W (1996) Endemic Tyrolean infantile cirrhosis: an ecogenetic disorder. Lancet 347, 877–880.CrossRefGoogle ScholarPubMed
Müller, T, Van de Sluis, B, Zhernakova, A, Van Binsbergen, E, Janecke, AR, Bavdekar, A et al. (2003) The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis. Journal of Hepatology 38, 164–168.CrossRefGoogle Scholar
Myers, BM, Prendergast, FG, Holman, R, Kuntz, SM & LaRusso, NF (1993) Alterations in hepatocyte lysosomes in experimental hepatic copper overload in rats. Gastroenterology 105, 1814–1823.CrossRefGoogle ScholarPubMed
Nakano, A, Marks, DL, Tietz, PS, de Groen, PC & LaRusso, NF (1995) Quantitative importance of biliary excretion to the turnover of hepatic lysosomal enzymes. Hepatology 22, 262–266.Google Scholar
Nanji, MS & Cox, DW (1999) The copper chaperone Atox1 in canine copper toxicosis in Bedlington terriers. Genomics 62, 108–112.CrossRefGoogle ScholarPubMed
Oude Elferink, RO & Groen, AK, (2002) Genetic defects in hepatobiliary transport. Biochimica et Biophysica Acta 1586, 129–145.CrossRefGoogle Scholar
Payne, AS & Gitlin, JD (1998) Functional expression of the Menkes disease protein reveals common biochemical mechanisms among the copper-transporting P-type ATPases. Journal of Biological Chemistry 273, 3765–3770.CrossRefGoogle ScholarPubMed
Petris, MJ, Smith, K, Lee, J & Thiele, DJ (2003) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. Journal of Biological Chemistry 278, 9639–9646.CrossRefGoogle ScholarPubMed
Petrukhin, K, Fischer, SG, Pirastu, M, Tanzi, RE, Chernov, I, Devoto, M, et al. (1993) Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nature Genetics 5, 338–343.CrossRefGoogle ScholarPubMed
Pufahl, RA, Singer, CP, Peariso, KL, Lin, SJ, Schmidt, PJ, Fahrni, CJ, Culotta, VC, Penner-Hahn, JE O'Halloran TV (1997) Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science 278, 853–856.CrossRefGoogle ScholarPubMed
Puig, S, Lee, J, Lau, M & Thiele, DJ (2002) Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake. Journal of Biological Chemistry 277, 26021–26030.CrossRefGoogle ScholarPubMed
Roelofsen, H, Wolters, H, Van Luyn, MJ, Miura, N, Kuipers, F & Vonk, RJ (2000) Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterology 119, 782–793.CrossRefGoogle ScholarPubMed
Su, LC, Ravanshad, S, Owen, CA >Jr McCall, JT Zollman, PE & Hardy, RM, (1982) A comparison of copper-loading disease in Bedlington terriers and Wilson's disease in humans. American Journal of Physiology 243, G226–G230.Google ScholarPubMed
Tanner, MS, Portmann, B, Mowat, AP, Williams, R, Pandit, AN, Mills, CF & Bremner, I (1979) Increased hepatic copper concentration in Indian childhood cirrhosis. Lancet i, 1203–1205.CrossRefGoogle Scholar
Tanzi, RE, Petrukhin, K, Chernov, I, Pellequer, JL, Wasco, W, Ross, B, et al. (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nature Genetics 5, 344–350.CrossRefGoogle Scholar
Trauner, M & Boyer, JL (2003) Bile salt transporters: molecular characterization, function, and regulation. Physiology Reviews 83, 633–671.CrossRefGoogle ScholarPubMed
Uetz, P, Giot, L, Cagney, G, Mansfield, TA, Judson, RS, Knight, JR et al. (2000) A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae. Nature 403, 623–627.CrossRefGoogle ScholarPubMed
Vanderwerf, SM, Cooper, MJ, Stetsenko, IV & Lutsenko, S (2001) Copper specifically regulates intracellular phosphorylation of the Wilson's disease protein, a human copper-transporting ATPase. Journal of Biological Chemistry 276, 36289–36294.CrossRefGoogle ScholarPubMed
Van de Sluis, BJ, Breen, M, Nanji, M, Van Wolferen, M, de Jong, P, Binns, MM, Pearson, PL, Kuipers, J, Rothuizen, J, Cox, DW, Wijmenga, C & Van Oost, BA (1999) Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16. Human Molecular Genetics 8, 501–507.CrossRefGoogle Scholar
Van de Sluis, B, Kole, S, Van Wolferen, M, Holmes, NG, Pearson, PL, Rothuizen, J, Van Oost, BA & Wijmenga, C (2000) Refined genetic and comparative physical mapping of the canine copper toxicosis locus. Mammalian Genome 11, 455–460.CrossRefGoogle ScholarPubMed
Van de Sluis, B, Nanji, MS, Breen, M, Pearson, PL, Oost, BA, Cox, DW & Wijmenga, C (2001) Characterization and chromosomal localization of five canine ATOX1 pseudogenes. Cytogenetics and Cell Genetics 93, 105–108.CrossRefGoogle ScholarPubMed
Van de Sluis, B, Rothuizen, J, Pearson, PL, Van Oost, BA & Wijmenga, C (2002) Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Human Molecular Genetics 11, 165–173.CrossRefGoogle Scholar
Vrana, KE, Freeman, WM & Aschner, M (2003) Use of microarray technologies in toxicology research. Neurotoxicology 24, 321–332.CrossRefGoogle ScholarPubMed
Vulpe, C, Levinson, B, Whitney, S, Packman, S & Gitschier, J, (1993) Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genetics 3, 7–13.CrossRefGoogle ScholarPubMed
Walker, JM, Tsivkovskii, R, Lutsenko, S, (2002) Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity. Journal of Biological Chemistry 277, 27953–27959.CrossRefGoogle Scholar
Waring, JF & Halbert, DN (2002) The promise of toxicogenomics. Current Opinion of Molecular Therapy 4, 229–235.Google ScholarPubMed
Wernimont, AK, Huffman, DL, Lamb, AL, O'Halloran, TV & Rosenzweig, AC, (2000) Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins. Nature Structural Biology 7, 766–771.Google ScholarPubMed
Yamaguchi, Y, Heiny, ME & Gitlin, JD, (1993) Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochemical and Biophysical Research Communications 197, 271–277.CrossRefGoogle ScholarPubMed
Yuzbasiyan-Gurkan, V, Blanton, SH, Cao, Y, Ferguson, P, Li, J, Venta, PJ & Brewer, GJ, (1997) Linkage of a microsatellite marker to the canine copper toxicosis locus in Bedlington terriers. American Journal of Veterinary Research 58, 23–27.CrossRefGoogle Scholar
Zhou, B & Gitschier, J (1997) hCTR1: a human gene for copper uptake identified by complementation in yeast. Proceedings of the National Academy of Sciences USA 94, 7481–7486.CrossRefGoogle ScholarPubMed