The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance
The metal ion transporter ZIP8 (SLC39A8) mediates cellular uptake of vital divalent metal ions. Genome-wide association studies (GWAS) showed that the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits, including reduced arterial blood pressure,...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-06-01
|
| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.912277/full |
| _version_ | 1828793703519485952 |
|---|---|
| author | Sophia N. Verouti Sophia N. Verouti Jonai Pujol-Giménez Jonai Pujol-Giménez Paola Bermudez-Lekerika Paola Bermudez-Lekerika Laeticia Scherler Laeticia Scherler Rajesh Bhardwaj Rajesh Bhardwaj Rajesh Bhardwaj Aurélien Thomas Aurélien Thomas Sébastien Lenglet Mark Siegrist Willy Hofstetter Daniel G. Fuster Daniel G. Fuster Matthias A. Hediger Matthias A. Hediger Geneviève Escher Geneviève Escher Bruno Vogt Bruno Vogt |
| author_facet | Sophia N. Verouti Sophia N. Verouti Jonai Pujol-Giménez Jonai Pujol-Giménez Paola Bermudez-Lekerika Paola Bermudez-Lekerika Laeticia Scherler Laeticia Scherler Rajesh Bhardwaj Rajesh Bhardwaj Rajesh Bhardwaj Aurélien Thomas Aurélien Thomas Sébastien Lenglet Mark Siegrist Willy Hofstetter Daniel G. Fuster Daniel G. Fuster Matthias A. Hediger Matthias A. Hediger Geneviève Escher Geneviève Escher Bruno Vogt Bruno Vogt |
| author_sort | Sophia N. Verouti |
| collection | DOAJ |
| description | The metal ion transporter ZIP8 (SLC39A8) mediates cellular uptake of vital divalent metal ions. Genome-wide association studies (GWAS) showed that the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits, including reduced arterial blood pressure, increased body mass index and hyperlipidemia. We analyzed in vitro the transport properties of mutant ZIP8 A391T and investigated in vivo in mice the physiological effects of this polymorphism. In vitro, the intrinsic transport properties of mutant ZIP8 were similar to those of wild type ZIP8, but cellular uptake of zinc, cadmium and iron was attenuated due to reduced ZIP8 plasma membrane expression. We then generated the ZIP8 A393T mice (ZIP8KI) that carry the corresponding polymorphism and characterized their phenotype. We observed lower protein expression in lung and kidney membrane extracts in ZIP8KI mice. The ZIP8KI mice exhibited striking changes in metal ion composition of the tissues, including cobalt, palladium, mercury and platinum. In agreement with GWAS, ZIP8KI mice showed reduced arterial blood pressure. Body weight and plasma lipid composition remained unchanged, although these features were reported to be increased in GWAS. ZIP8KI mice also exhibited remarkable insulin resistance and were protected from elevated blood glucose when challenged by dietary sucrose supplementation. We showed that increased hepatic insulin receptor expression and decreased ZnT8 (slc30a8) metal ion transporter mRNA expression are associated with this phenotypic change. In conclusion, our data reveal that ZIP8 plays an important role in blood pressure regulation and glucose homeostasis. |
| first_indexed | 2024-12-12T03:31:05Z |
| format | Article |
| id | doaj.art-4dd0962652ae49ec91bde16de4444a7d |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-12T03:31:05Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-4dd0962652ae49ec91bde16de4444a7d2022-12-22T00:39:54ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-06-011310.3389/fphys.2022.912277912277The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin ResistanceSophia N. Verouti0Sophia N. Verouti1Jonai Pujol-Giménez2Jonai Pujol-Giménez3Paola Bermudez-Lekerika4Paola Bermudez-Lekerika5Laeticia Scherler6Laeticia Scherler7Rajesh Bhardwaj8Rajesh Bhardwaj9Rajesh Bhardwaj10Aurélien Thomas11Aurélien Thomas12Sébastien Lenglet13Mark Siegrist14Willy Hofstetter15Daniel G. Fuster16Daniel G. Fuster17Matthias A. Hediger18Matthias A. Hediger19Geneviève Escher20Geneviève Escher21Bruno Vogt22Bruno Vogt23Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandSignal Transduction Laboratory, National Institute of Environmental Health Sciences, NIH, Durham, NC, United StatesForensic Toxicology and Chemistry Unit, CURML, Lausanne University Hospital, Geneva University, Geneva, SwitzerlandFaculty Unit of Toxicology, CURML, Faculty of Biology and Medicine, University of Lausanne, Lausanne, SwitzerlandForensic Toxicology and Chemistry Unit, CURML, Lausanne University Hospital, Geneva University, Geneva, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandThe metal ion transporter ZIP8 (SLC39A8) mediates cellular uptake of vital divalent metal ions. Genome-wide association studies (GWAS) showed that the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits, including reduced arterial blood pressure, increased body mass index and hyperlipidemia. We analyzed in vitro the transport properties of mutant ZIP8 A391T and investigated in vivo in mice the physiological effects of this polymorphism. In vitro, the intrinsic transport properties of mutant ZIP8 were similar to those of wild type ZIP8, but cellular uptake of zinc, cadmium and iron was attenuated due to reduced ZIP8 plasma membrane expression. We then generated the ZIP8 A393T mice (ZIP8KI) that carry the corresponding polymorphism and characterized their phenotype. We observed lower protein expression in lung and kidney membrane extracts in ZIP8KI mice. The ZIP8KI mice exhibited striking changes in metal ion composition of the tissues, including cobalt, palladium, mercury and platinum. In agreement with GWAS, ZIP8KI mice showed reduced arterial blood pressure. Body weight and plasma lipid composition remained unchanged, although these features were reported to be increased in GWAS. ZIP8KI mice also exhibited remarkable insulin resistance and were protected from elevated blood glucose when challenged by dietary sucrose supplementation. We showed that increased hepatic insulin receptor expression and decreased ZnT8 (slc30a8) metal ion transporter mRNA expression are associated with this phenotypic change. In conclusion, our data reveal that ZIP8 plays an important role in blood pressure regulation and glucose homeostasis.https://www.frontiersin.org/articles/10.3389/fphys.2022.912277/fullZIP8blood pressureglucoseSLC39A8rs13107325divalent metal ions |
| spellingShingle | Sophia N. Verouti Sophia N. Verouti Jonai Pujol-Giménez Jonai Pujol-Giménez Paola Bermudez-Lekerika Paola Bermudez-Lekerika Laeticia Scherler Laeticia Scherler Rajesh Bhardwaj Rajesh Bhardwaj Rajesh Bhardwaj Aurélien Thomas Aurélien Thomas Sébastien Lenglet Mark Siegrist Willy Hofstetter Daniel G. Fuster Daniel G. Fuster Matthias A. Hediger Matthias A. Hediger Geneviève Escher Geneviève Escher Bruno Vogt Bruno Vogt The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance Frontiers in Physiology ZIP8 blood pressure glucose SLC39A8 rs13107325 divalent metal ions |
| title | The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance |
| title_full | The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance |
| title_fullStr | The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance |
| title_full_unstemmed | The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance |
| title_short | The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance |
| title_sort | allelic variant a391t of metal ion transporter zip8 slc39a8 leads to hypotension and enhanced insulin resistance |
| topic | ZIP8 blood pressure glucose SLC39A8 rs13107325 divalent metal ions |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.912277/full |
| work_keys_str_mv | AT sophianverouti theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT sophianverouti theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT jonaipujolgimenez theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT jonaipujolgimenez theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT paolabermudezlekerika theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT paolabermudezlekerika theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT laeticiascherler theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT laeticiascherler theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT rajeshbhardwaj theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT rajeshbhardwaj theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT rajeshbhardwaj theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT aurelienthomas theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT aurelienthomas theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT sebastienlenglet theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT marksiegrist theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT willyhofstetter theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT danielgfuster theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT danielgfuster theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT matthiasahediger theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT matthiasahediger theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT genevieveescher theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT genevieveescher theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT brunovogt theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT brunovogt theallelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT sophianverouti allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT sophianverouti allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT jonaipujolgimenez allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT jonaipujolgimenez allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT paolabermudezlekerika allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT paolabermudezlekerika allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT laeticiascherler allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT laeticiascherler allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT rajeshbhardwaj allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT rajeshbhardwaj allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT rajeshbhardwaj allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT aurelienthomas allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT aurelienthomas allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT sebastienlenglet allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT marksiegrist allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT willyhofstetter allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT danielgfuster allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT danielgfuster allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT matthiasahediger allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT matthiasahediger allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT genevieveescher allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT genevieveescher allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT brunovogt allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance AT brunovogt allelicvarianta391tofmetaliontransporterzip8slc39a8leadstohypotensionandenhancedinsulinresistance |