title: ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report.
abstract: OBJECTIVE
  Mutations in ABCC6 underlie the ectopic mineralization disorder pseudoxanthoma elasticum (PXE) and some forms of generalized arterial calcification of infancy, both of which affect the cardiovascular system. Using cultured cells, we recently showed that ATP-binding cassette subfamily C member 6 (ABCC6) mediates the cellular release of ATP, which is extracellularly rapidly converted into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi). The current study was performed to determine which tissues release ATP in an ABCC6-dependent manner in vivo, where released ATP is converted into AMP and PPi, and whether human PXE ptients have low plasma PPi concentrations.
  
  
  RESULTS
  Using cultured primary hepatocytes and in vivo liver perfusion experiments, we found that ABCC6 mediates the direct, sinusoidal, release of ATP from the liver. Outside hepatocytes, but still within the liver vasculature, released ATP is converted into AMP and PPi. The absence of functional ABCC6 in patients with PXE leads to strongly reduced plasma PPi concentrations.
  
  
  CONCLUSIONS
  Hepatic ABCC6-mediated ATP release is the main source of circulating PPi, revealing an unanticipated role of the liver in systemic PPi homeostasis. Patients with PXE have a strongly reduced plasma PPi level, explaining their mineralization disorder. Our results indicate that systemic PPi is relatively stable and that PXE, generalized arterial calcification of infancy, and other ectopic mineralization disorders could be treated with PPi supplementation therapy.
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Robert S
authors: RS
authors: Jansen
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Suzanne
authors: S
authors: Duijst
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Sunny
authors: S
authors: Mahakena
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Daniela
authors: D
authors: Sommer
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Flóra
authors: F
authors: Szeri
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: András
authors: A
authors: Váradi
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Astrid
authors: A
authors: Plomp
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Arthur A
authors: AA
authors: Bergen
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Ronald P J
authors: RP
authors: Oude Elferink
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.).
authors: Piet
authors: P
authors: Borst
authors: From the Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands (R.S.J., S.M., D.S., P.B., K.v.d.W.); Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.D., R.P.J.O.E.); Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary (F.S., A.V.); Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands (A.P., A.A.B.); and Netherlands Institute for Neuroscience, Amsterdam, The Netherlands (A.A.B.). k.vd.wetering@nki.nl.
authors: Koen
authors: K
authors: van de Wetering
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000249:Adenosine Monophosphate / Q000097:blood; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D011756:Diphosphates / Q000097:blood*; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D011561:Pseudoxanthoma Elasticum / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D018528:ATP-Binding Cassette Transporters; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D017077:Culture Media, Conditioned; D011756:Diphosphates; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human; C504743:Abcc6 protein, mouse; C107241:diphosphoric acid
keywords: multidrug resistance-associated proteins; nucleotides; pathologic calcification; pyrophosphatases; vascular calcification