Cardiac copper deficiency activates a systemic signaling mechanism that communicates with the copper acquisition and storage organs.
Copper (Cu) is an essential cofactor for a variety of metabolic functions, and the regulation of systemic Cu metabolism is critical to human health. Dietary Cu is absorbed through the intestine, stored in the liver, and mobilized into the circulation; however, systemic Cu homeostasis is poorly understood. We generated mice with a cardiac-specific knockout of the Ctr1 Cu transporter (Ctr1(hrt/hrt)), resulting in cardiac Cu deficiency and severe cardiomyopathy. Unexpectedly, Ctr1(hrt/hrt) mice exhibited increased serum Cu levels and a concomitant decrease in hepatic Cu stores. Expression of the ATP7A Cu exporter, thought to function predominantly in intestinal Cu acquisition, was strongly increased in liver and intestine of Ctr1(hrt/hrt) mice. These studies identify ATP7A as a candidate for hepatic Cu mobilization in response to peripheral tissue demand, and illuminate a systemic regulation in which the Cu status of the heart is signaled to organs that take up and store Cu.
Kim
Byung-Eun
BE
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Turski
Michelle L
ML
Nose
Yasuhiro
Y
Casad
Michelle
M
Rockman
Howard A
HA
Thiele
Dennis J
DJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000172:deficiency / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D004330:Drosophila / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D015398:Signal Transduction
C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490077:Slc31a1 protein, mouse; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases
J Histochem Cytochem. 2008 Apr;56(4):389-99
18180385
Nat Rev Mol Cell Biol. 2008 Jan;9(1):72-81
17987043
Circulation. 2007 Jan 2;115(1):94-102
17190866
Nat Rev Mol Cell Biol. 2003 Jul;4(7):566-77
12838339
Cell Metab. 2006 Sep;4(3):235-44
16950140
Curr Opin Gastroenterol. 2007 Mar;23(2):187-92
17268249
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6700-5
12754378
Science. 2004 Dec 17;306(5704):2090-3
15514116
DNA Cell Biol. 2002 Apr;21(4):259-70
12042066
Am J Hypertens. 2002 Jun;15(6):513-7
12074352
Nucleic Acids Res. 1999 Nov 15;27(22):4324-7
10536138
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1215-20
12538877
J Biol Chem. 2002 Nov 29;277(48):46632-8
12351628
Circ Res. 2000 Feb 18;86(3):264-9
10679476
Circ Res. 2003 Jun 13;92(11):1171-5
12805233
Nature. 1996 Oct 3;383(6599):434-7
8837775
J Histochem Cytochem. 1999 Dec;47(12):1553-62
10567439
Comp Biochem Physiol C Toxicol Pharmacol. 2008 Apr;147(3):316-23
18178529
Hypertension. 2008 Nov;52(5):945-51
18768397
Biochim Biophys Acta. 2006 Jul;1763(7):759-72
16631971
Cell Metab. 2008 Jul;8(1):1-3
18590684
J Biol Inorg Chem. 2010 Jan;15(1):107-13
19856191
J Card Fail. 2002 Dec;8(6 Suppl):S258-63
12555129
Am J Clin Nutr. 1998 May;67(5 Suppl):960S-964S
9587136
Nat Chem Biol. 2008 Mar;4(3):176-85
18277979
J Clin Invest. 1997 Jul 1;100(1):169-79
9202069
Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3101-12
11087268
J Biol Chem. 2003 Apr 4;278(14):12278-84
12529325
Nutrition. 2000 Jul-Aug;16(7-8):502-4
10906536
Cardiology. 2002;97(2):73-8
11978952
Circ Res. 2001 Jul 6;89(1):20-5
11440973
Annu Rev Physiol. 2003;65:45-79
12524460
J Trace Elem Med Biol. 2001 Apr;14(4):237-40
11396784
Exp Mol Pathol. 1974 Feb;20(1):40-56
4361723
J Bioenerg Biomembr. 2007 Dec;39(5-6):403-7
18000748
Biochim Biophys Acta. 2006 Jul;1763(7):747-58
16828895
J Nutr. 1983 Oct;113(10):2048-58
6312000
Oncogene. 2005 Jan 13;24(3):367-80
15531919
J Biol Chem. 1991 Dec 25;266(36):24613-20
1722208
Trends Biochem Sci. 2006 Nov;31(11):604-7
16982196
J Biol Chem. 2009 Dec 4;284(49):33949-56
19808669
Blood. 2007 May 1;109(9):4038-44
17218383
Proc Soc Exp Biol Med. 1993 Jul;203(3):262-73
8516340
Arch Biochem Biophys. 2007 Jul 15;463(2):134-48
17562324
J Nutr. 2006 Jan;136(1):21-6
16365053
Exp Biol Med (Maywood). 2004 Sep;229(8):756-64
15337829
Hum Mol Genet. 2000 Mar 22;9(5):795-801
10749987
J Biol Chem. 2007 Aug 17;282(33):24017-26
17573340
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1394-9
16432241
Arch Biochem Biophys. 2008 Aug 1;476(1):22-32
18534184
J Exp Med. 2007 Mar 19;204(3):657-66
17339407
Annu Rev Neurosci. 2007;30:317-37
17367269
Comp Biochem Physiol C Toxicol Pharmacol. 2007 Mar;145(2):275-81
17287146
J Biol Chem. 2006 May 12;281(19):13581-13587
16531609
J Nutr. 1982 Nov;112(11):2142-50
6215471
Biometals. 2006 Oct;19(5):555-64
16937262
Biochem J. 2007 Mar 1;402(2):241-50
17109627
Hum Mol Genet. 2000 Nov 22;9(19):2845-51
11092760
J Biol Chem. 2003 Sep 12;278(37):35071-8
12832419
Genes Nutr. 2006 Mar;1(1):51-9
18850220
FEBS Lett. 1994 Sep 5;351(2):186-90
8082762