Targeted disruption of the PDZK1 gene in mice causes tissue-specific depletion of the high density lipoprotein receptor scavenger receptor class B type I and altered lipoprotein metabolism

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dc.contributor.authorKocher, O
dc.contributor.authorYesilaltay, A
dc.contributor.authorCirovic, C
dc.contributor.authorPal, R
dc.contributor.authorRigotti, A
dc.contributor.authorKrieger, M
dc.date.accessioned2024-01-10T12:09:10Z
dc.date.available2024-01-10T12:09:10Z
dc.date.issued2003
dc.description.abstractPDZK1, a multi-PDZ domain containing adaptor protein, interacts with various membrane proteins, including the high density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI). Here we show that PDZK1 controls in a tissue-specific and post-transcriptional fashion the expression of SR-BI in vivo. SR-BI protein expression in PDZK1 knock-out (KO) mice was reduced by 95% in the liver, 50% in the proximal intestine, and not affected in steroidogenic organs (adrenal, ovary, and testis). Thus, PDZK1 joins a growing list of adaptors that control tissue-specific activity of cell surface receptors. Hepatic expression of SR-BII, a minor splice variant with an alternative C-terminal cytoplasmic domain, was not affected in PDZK1 KO mice, suggesting that binding of PDZK1 to SR-BI is required for controlling hepatic SR-BI expression. The loss of hepatic SR-BI was the likely cause of the elevation in plasma total and HDL cholesterol and the increase in HDL particle size in PDZK1 KO mice, phenotypes similar to those observed in SR-BI KO mice. PDZK1 KO mice differed from SR-BI KO mice in that the ratio of unesterified to total plasma cholesterol was normal, females were fertile, and cholesteryl ester stores in steroidogenic organs were essentially unaffected. These differences may be due to nearly normal extrahepatic expression of SR-BI in PDZK1 KO mice. The PDZK1-dependent regulation of hepatic SR-BI and, thus, lipoprotein metabolism supports the proposal that this adaptor may represent a new target for therapeutic intervention in cardiovascular disease.
dc.description.funderFIC NIH HHS
dc.description.funderNHLBI NIH HHS
dc.description.funderFOGARTY INTERNATIONAL CENTER
dc.description.funderNATIONAL HEART, LUNG, AND BLOOD INSTITUTE
dc.fechaingreso.objetodigital2024-04-25
dc.format.extent6 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1074/jbc.M310482200
dc.identifier.issn0021-9258
dc.identifier.pubmedidMEDLINE:14551195
dc.identifier.urihttps://doi.org/10.1074/jbc.M310482200
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/76464
dc.identifier.wosidWOS:000187480700101
dc.information.autorucMedicina;Rigotti A;S/I;68489
dc.issue.numero52
dc.language.isoen
dc.nota.accesocontenido completo
dc.pagina.final52825
dc.pagina.inicio52820
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.revistaJOURNAL OF BIOLOGICAL CHEMISTRY
dc.rightsacceso abierto
dc.subjectAUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA
dc.subjectDOMAIN-CONTAINING PROTEIN
dc.subjectSR-BI
dc.subjectLIPID-METABOLISM
dc.subjectHUMAN CARCINOMAS
dc.subjectADAPTER PROTEIN
dc.subjectDOWN-REGULATION
dc.subjectLDL RECEPTOR
dc.subjectIDENTIFICATION
dc.subjectEXPRESSION
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleTargeted disruption of the PDZK1 gene in mice causes tissue-specific depletion of the high density lipoprotein receptor scavenger receptor class B type I and altered lipoprotein metabolism
dc.typeartículo
dc.volumen278
sipa.codpersvinculados68489
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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