Punicalagin, an active component in pomegranate ... - Nature

Of the polyphenols found in pomegranate, punicalagin (PU), the most abundant ellagitannin with the highest molecular weight, has been shown to ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature scientificreports articles article Punicalagin,anactivecomponentinpomegranate,amelioratescardiacmitochondrialimpairmentinobeseratsviaAMPKactivation DownloadPDF DownloadPDF Subjects MetabolicdisordersNutrition AbstractObesityisassociatedwithanincreasingprevalenceofcardiovasculardiseasesandmetabolicsyndrome.Itisofparamountimportancetoreduceobesity-associatedcardiacdysfunctionandimpairedenergymetabolism.Inthisstudy,theactivationoftheAMP-activatedproteinkinase(AMPK)pathwaybypunicalagin(PU),amajorellagitannininpomegranatewasinvestigatedintheheartofaratobesitymodel.InmaleSDrats,eight-weekadministrationof150mg/kgpomegranateextract(PE)containing40%punicalaginsufficientlypreventedhigh-fatdiet(HFD)-inducedobesityassociatedaccumulationofcardiactriglycerideandcholesterolaswellasmyocardialdamage.Concomitantly,theAMPKpathwaywasactivated,whichmayaccountforpreventionofmitochondriallossviaupregulatingmitochondrialbiogenesisandameliorationofoxidativestressviaenhancingphaseIIenzymesintheheartsofHFDrats.Togetherwiththenormalizedexpressionofuncouplingproteinsandmitochondrialdynamicregulators,PEsignificantlypreventedHFD-inducedcardiacATPloss.Throughinvitrocultures,weshowedthatpunicalaginwasthepredominantcomponentthatactivatedAMPKbyquicklydecreasingthecellularATP/ADPratiospecificallyincardiomyocytes.Ourfindingsdemonstratedthatpunicalagin,themajoractivecomponentinPE,couldmodulatemitochondriaandphaseIIenzymesthroughAMPKpathwaytopreventHFD-inducedcardiacmetabolicdisorders. IntroductionAsaleadingcauseofpreventabledeathworldwide,obesityhasincreasedinprevalenceinbothadultsandchildrenandhasbecomeoneofthemostseriouspublichealthproblems1.Previousstudiessuggestthatobesityiscloselyassociatedwithcardiovasculardisorders,includingcardiacdysfunction,whichisassumedtobetheconsequenceofadaptiontotheoversupplyofsubstratessuchaslong-termexposuretoahigh-fatdiet(HFD)2,3.Increasedbodyweightgaincausesthehearttoswitchfromfattyacidburningtosugarburningwiththeconsequenceoffataccumulationaroundtheheart,whicheventuallyinducescardiacimpairmentandincreasestheriskofmyocardialinfarction4,5.Inadditiontofataccumulation,severalotherriskfactorssuchasoxidativestress6,7andmitochondrialdysfunction8havealsobeenreportedtobecloselyassociatedwithobesity-inducedcardiacmetabolicdisordersandimpairment.PreviousstudyindicatedthatexcessivefataccumulationcouldamplifyROSgenerationandestablishoxidativestressandmorphologicalchanges,whicheventuallyresultsinheartinjury9.HFDcouldresultinbothadecreaseinthemitochondrialquininepoolandaprofoundmodificationinthecompositionofmitochondriallipids,leadingtotheinhibitionoffattyacidoxidationandincreasedmitochondrialROSproduction10.AMP-activatedproteinkinase(AMPK),themajorcellularenergysensor,wasrecentlyidentifiedasmasterregulatorofmitochondrialbiogenesis11,12anditsactivitywassuppressedbyHFDinmultipletissuesincludingwhiteadiposetissue,heartandliver13.HFDinducedAMPKactivitylosswasreportedtoenhancecardiomyocytedeathduringmyocardialischemia14.ThedeficiencyofAMPKcouldexaggerateHFDinducedcardiachypertrophyandcontractiledysfunction15.While,theknowledgeonAMPKregulatedmitochondrialbiogenesisinHFDheartislimitedandrequiresfurtherinvestigation.Inadditiontomitochondrialbiogenesis,recentstudysuggestedthatAMPKcouldmodulateoxidativestressthroughNF-E2relatedfactor(Nrf2)mediatedphaseIIantioxidantenzymesandthepotentialcrosstalkhasbeenreportedinCaenorhabditiselegans16,humanendothelialcells17andmammalianinflammatorysystems18.Inourpreviousstudy,weobservedthatAMPKcouldcoordinatebothperoxisomeproliferator-activatedreceptorgammacoactivator-1alpha(PGC-1α)mediatedmitochondrialbiogenesisandNrf2mediatedphaseIIenzymestoreduceoxidativestressforneuroprotectiveeffect19.HereweproposedthatdisruptionofAMPK-PGC-1α/Nrf2cascadesmightbethemajorcontributiontoHFD-inducedoxidativestressandcardiacimpairment.Punicagranatum,commonlyknownaspomegranate,havebecomeincreasingpopularbecauseoftheirimportantbiologicalactions20,includingcardiovascularprotection21.Pomegranatejuicehasbeendemonstratedtoimprovethelipidprofilesindiabeticpatientswithhyperlipidemia22.Pomegranateflowerextractwasreportedtoimprovecardiaclipidmetabolismanddiminishcardiacfibrosisindiabeticrats23,24.Ofthepolyphenolsfoundinpomegranate,punicalagin(PU),themostabundantellagitanninwiththehighestmolecularweight,hasbeenshowntohaveantioxidantandanti-inflammatorybioactivities25,26.However,thecontributionsofPUinpomegranateassociatedcardiacbenefitsremainlargelyunknown.Incurrentstudy,weinvestigatethepotentialeffectsandunderlyingmechanismofPUonHFD-inducedcardiacimpairment,withaspecificfocusontheAMPK-PGC-1α/Nrf2cascade.ResultsObesityassociatedheartmetabolicchangesAnHFDratmodelwasusedtoinvestigatehowobesityaffectscardiacmetabolismandpotentialbenefitsofPU.ObesitywasinducedbyaHFDoveran8-weekperiod.Sincelargeamountof100%PUforanimalsupplementwasnotavailable,naturalPEcontaining40%PUwasadministratedthroughoralgavageatadosageof150 mg/kg/dayduringtheHFDperiod.AsshowninFig.1A–C,theHFDsignificantlyincreasedbodyweightandbodyweightgain,whichwasefficientlyreducedbyPE.Nosignificantchangeswereobservedamongthethreegroupsregardingfoodintake(Fig.1D).ItisinterestingthatPEshowednoeffectonHFDinducedperirenalfatandepididymalfatincrease(Fig.S1).HearttissueanalysisshowedhighertriglycerideandcholesterollevelsintheHFDgroup,whichwerenormalizedbyPEsupplement(Fig.1E,F).Serumenzymeactivitiesofcreatinekinase(CK)andlactatedehydrogenase(LDH)areusuallyconsideredmarkersofcardiacfunctionandtheiractivitieswouldbemorethan10timeshigherincardiacdysfunctionrats27,28.IncurrentHFDfeeding,onlyslightincreaseswereobservedonserumCKandLDHactivitiesaswellasLDHproductlactate,whichallweresufficientlydecreasedbyPEsupplement(Fig.1G–I).Figure1EffectofPEandHFDonobesity-associatedmetabolicchangesintheheart.SDratsintheHFDgroupswereadministeredeithersalineorPE(150 mg/kg/day)for8weeks.(A)Weeklybodyweight.(B)Finalbodyweight.(C)Bodyweightgain.(D)Foodintake.(E)Triglycerideand(F)cholesterolinhearttissues.(G)CKactivity,(H)LDHactivityand(I)lactatecontentinratserum.Thevaluesarepresentedasthemeans ± S.E.M.(n = 10);*p