A Concerted Kinase Interplay Identifies PPARγ as a Molecular Target of Ghrelin Signaling in Macrophages 英文参考文献.docVIP
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A Concerted Kinase Interplay Identifies PPARγ as a Molecular Target of Ghrelin Signaling in Macrophages 英文参考文献
AConcertedKinaseInterplayIdentifiesPPARcasa
MolecularTargetofGhrelinSignalinginMacrophages
AnnieDemers1,2.,Ve′roniqueCaron1,3.,Ame′lieRodrigue-Way1,3,WalterWahli4,HuyOng2,Andre′
Tremblay1,3,5
*
1Research Center, CHU Ste-Justine, University of Montreal, Montre′al, Que′bec, Canada, 2Faculty of Pharmacy, University of Montreal, Montre′al, Que′bec, Canada,
3Department of Biochemistry, University of Montreal, Montre′al, Que′bec, Canada, 4Center for Integrative Genomics, National Research Center Frontiers in Genetics,
UniversityofLausanne,Lausanne,Switzerland,5DepartmentofObstetricsGynecology,UniversityofMontreal,Montre′al,Que′bec, Canada
Abstract
Theperoxisomeproliferator-activatorreceptorPPARcplaysanessentialroleinvascularbiology,modulatingmacrophage
functionandatherosclerosisprogression.Recently,wehavedescribedthebeneficialeffectofcombinedactivationofthe
ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through
transcriptionalactivationofPPARc.AlthoughtheinterplaybetweenCD36andPPARcinatherogenesisiswellrecognized,
thecontributionoftheghrelinreceptortoregulatePPARcremainsunknown.Here,wedemonstratethatghrelintriggers
PPARcactivationthroughaconcertedsignalingcascadeinvolvingErk1/2andAktkinases,resultinginenhancedexpression
of downstream effectors LXRa and ABC sterol transporters in human macrophages. These effects were associated with
enhanced PPARc phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was
identifiedasbeingrecruitedtoGHS-R1ainresponsetoghrelin,butfailureofactivatedFyntoenhancePPARcSer-84specific
phosphorylationreliedontheconcomitantrecruitmentofdockingproteinDok-1,whichpreventedoptimalactivationof
the Erk1/2pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARc activity and responsiveness to Src
inhibition,supportingamechanismindependentofSer-84inPPARcresponsetoghrelin.Consistentwiththis,wefoundthat
ghrelin promoted the PI3-K/Akt pathway in
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