<database>
<name>MetaboLights</name>
<description>a database for metabolomics experiments and derived information</description>
<release>1</release>
<release_date>2015-03-12</release_date>
<entry_count>1</entry_count>
<entries>
<entry id="MTBLS61">
<name>LC-MS metabolic profiling of mouse plasma and cell culture medium in relation to ABCC6 expression</name>
<description>Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ABCC6 (MRP6), an ATP-dependent efflux transporter that is mainly present in the liver. Abcc6-/- mice have been instrumental in the demonstration that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE remained a mystery. We now show that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium of HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself did not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyzed the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data was demonstrated in Abcc6-/- mice, which had plasma PPi levels that were less than 40% of those found in wild-type mice. This study provides the first insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an as yet unidentified, but ABCC6-dependent mechanism.</description>
<cross_references>
<ref dbkey="" dbname="chebi" />
<ref dbkey="CHEBI:16857" dbname="chebi" />
</cross_references>
<dates>
<date value="2013-11-14" type="creation" />
<date value="2013-11-14" type="last_modification" />
</dates>
<additional_fields>
<field name="study_description">Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ABCC6 (MRP6), an ATP-dependent efflux transporter that is mainly present in the liver. Abcc6-/- mice have been instrumental in the demonstration that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE remained a mystery. We now show that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium of HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself did not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyzed the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data was demonstrated in Abcc6-/- mice, which had plasma PPi levels that were less than 40% of those found in wild-type mice. This study provides the first insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an as yet unidentified, but ABCC6-dependent mechanism.</field>
<field name="study_design">metabolite profiling</field>
<field name="study_design">nucleotides</field>
<field name="study_design">pseudoxanthoma elasticum</field>
<field name="study_design">multidrug resistance-associated protein 6</field>
<field name="study_design">ABCC6</field>
<field name="study_factor">ABCC6 genotype -/-</field>
<field name="study_factor">ABCC6 genotype rABCC6 overexpression</field>
<field name="study_factor">ABCC6 genotype +/+</field>
<field name="study_factor">ABCC6 genotype Endogenous background</field>
<field name="study_factor">Ectonucleotidase inhibition Control</field>
<field name="study_factor">Ectonucleotidase inhibition ARL67156+AMP-PCP</field>
<field name="study_factor">Gender Female</field>
<field name="study_factor">ABCC6 genotype hABCC6 overexpression</field>
<field name="study_factor">Gender Male</field>
<field name="study_factor">Ectonucleotidase inhibition Ectonucleotidase inhibition</field>
<field name="technology_type">mass spectrometry</field>
<field name="submitter">Robert Jansen</field>
<field name="platform">LTQ Orbitrap Discovery (Thermo Scientific)</field>
<field name="organism">HEK293</field>
<field name="organism">C57BL/6</field>
<field name="study_status">0</field>
</additional_fields>
</entry>
</entries>
</database>
baimingze
commented
9 years ago