Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia 2021 Hana Malinská.pdf

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InternationalJournalof
MolecularSciences
Article
Ovariectomy-InducedHepaticLipidandCytochromeP450
DysmetabolismPrecedesSerumDyslipidemia
HanaMalinská1,*,MartinaHüttl1,DenisaMiklánková1,JaroslavaTrnovská1,IvetaZapletalová2,
MartinPoruba2andIrenaMarková1
1CentreforExperimentalMedicine,InstituteforClinicalandExperimentalMedicine,
14021Prague,CzechRepublic;martina.******@(.);denisa.******@(.);
jaroslava.******@(.);******@(.)
2DepartmentofPharmacology,FacultyofMedicineandDentistry,PalackyUniversity,
77900Olomouc,CzechRepublic;iveta.******@(.);martin.******@(.)
*Correspondence:hana.******@;Tel.:+420-261-365-369;Fax:+420-261-363-027
Abstract:Ovarianhormonedeflciencyleadstoincreasedbodyweight,visceraladiposity,fattyliver

mechanismsofthesedisordersintheirearlyphasesofdevelopment,weinvestigatedtheeffectof
-operatedcontrols,ovariectomized
Wistarfemaleratsmarkedlyincreasedwholebodyandvisceraladiposetissueweight(p<)and
(p<)
afterovariectomyprecededchangesinbothserumlipidsandglucoseintolerance,reflectingalter-



(p<)anddecreasedCYP4A(p<)after



Citation:Malinská,H.;Hüttl,M.;
Miklánková,D.;Trnovská,J.;metabolismandsecretionfromthelivercontributedtohepatictriglycerideaccumulationinresponse
Zapletalová,I.;Poruba,M.;Marková,,interscapularbrownadiposetissueofovariectomizedratsexhibited
-InducedHepaticdecreasedfattyacidoxidation(p<),lipogenesis(p<)andlipolysis(p<)despitean
-
DysmetabolismPrecedesSerumregulationofsomeCYP450proteinsmayhavebeeninvolvedinthedevelopmentofhepaticsteatosis.
,22,Thelowmetabolicactivityofbrownadiposetissuemayhavecontributedtovisceraladiposityas
:///wellastriglycerideaccumulationduringthepostmenopausalperiod.
ijms22094527
Keywords:ovariectomy;metabolicsyndrome;brownadiposetissue;hepaticsteatosis;obesity;
AcademicEditor:MontserratEsteveinsulinresistance;methylglyoxal
Received:26March2021
Accepted:23April2021
Published:26April2021

Publisher’sNote:MDPIstaysneutralPostmenopausalwomenarehighlysusceptibletometabolicsyndrome,type2diabetes
withregardtojurisdictionalclaimsinandcardiovasculardisease[1,2].Prevalenceofmetabolicsyndromeinpostmenopausal
publishedmapsandinstitutionalaffll-womenis60%comparedto20%
,insulinresistance,fattyliverand

menopausesuggeststhatdisruptionofovarianfunctionmaycontributetotheincidenceof
,theunderlyingmechanismsremainunclear.
Copyright:©
LicenseeMDPI,Basel,,includingglucoseandlipidmetabolism,bodyweight,adipose
Thisarticleisanopenaccessarticletissuedistribution,caloricintakeandenergyexpenditure[3].
distributedunderthetermsandOvarianhormonescontributetothemaintenanceofinsulinsensitivityinwhiteadi-
conditionsoftheCreativeCommonsposetissue(WAT),preventinglow-gradeinflammationofWAT[4]independentlyofenergy
Attribution(CCBY)license(,itdoesnotseemto
(OVX)femalerats[5].Alterationsin
/).glucoseandlipidhomeostasismayprecedeincreasedbodyweightgainaftermenopause.
,22,:///ijms22094527:.
,22,45272of14
Increasingevidenceindicatesthatbrownadiposetissue(BAT)hasacriticalrolein
controllingenergymetabolism,anactivitypossiblyregulatedbysexualhormones[6].The
thermogenicabilityofBAThaspromptedresearchintothepositiveinfluencesofBATon
bodyweightregulationandglucoseandlipidhomeostasis[7].Oneproposedtherapeutic
strategyinvolvesaugmentingtheoxidativemetabolismofBAT[8].
Postmenopausalwomendisplayincreasedincidenceofhepaticsteatosisanddis-
ruptedlipidhomeostasis[9].Dysregulatedlipidmetabolisminturnaffectsbodyfatmass,
adiposity,
metabolism,regulationandtransport,estrogensignalingintheliverisimportantinpre-

androgensareunderstoodtoregulatetheexpressionandactivityofenzymesinvolved
(CYP)proteinfamilycontainsim-
portantenzymesinvolvedinxenobiotics,endogenouscompoundmetabolismandlipid
,CYP4Acatalyzesomega
hydroxylationoftheendogenousfattyacidsandprostaglandinsthatregulatemanyphysi-
ologicalfunctions[10,11].ChangesinthegeneregulationandexpressionofCYPslikely
reflecttheearlystageofNAFLDandmaybebeneflcialintreatinghepaticsteatosis.
Someofthefactorsinvolvedinthepathogenesisofhepaticsteatosisincludehepaticin-
sulinresistance,thepro-inflammatorypathwayandoxidativeaswellas(recently)carbonyl

ofdicarbonylslikemethylglyoxalmayincreaseoxidativestressintheliver,activatethe
inflammatorypathwayandplayakeyroleinthedevelopmentofothermetabolicdisorders
associatedwithpostmenopausalmetabolicsyndrome[12].
However,theexactmechanismsinvolvedintheearlystagesofovariectomy-induced
lipiddysmetabolism,includingtheirrelationstocirculatingserumlipidsandwholebody
energymetabolism,
mechanismsofdisordersassociatedwithovariectomy-inducedmetabolicsyndrome,we
examinedtheeffectofovariectomyontissuemetabolicdisturbanceslinkedtometabolic

impairedcytochromeP450familyproteins.

Beforeovariectomyanduponstartingthetrial,nodifferencesininitialbodyweight
(2437g),glucose()orserumtriglycerides
()wereobservedbetweentheexperimentalgroups.
,Adiposity,GlucoseToleranceandInsulinSensitivity
Asexpected,ovariectomyinfemaleWistarratswasassociatedwithdecreasedserum
levelsofthesexhormones17-estradioland17-hydroxyprogesterone(Table1).Inkeeping
withtheinhibitoryeffectofestradiolonappetite,ovariectomizedfemaleratsexhibited
higherfoodintake(+9%,p<)(Figure1)andmarkedlyincreasedserumlevelsofleptin.
Nochangesintheappetitehormoneghrelinwereobserved(Table1).
(W–OVX)ratscompared
tosham-operatedcontrolrats(W–sham).
W–ShamW–OVXp<
Initialbodyweight(g)24318253.
Finalbodyweight(g)29224346
Visceraladiposetissueweight(g/100g)
Brownadiposetissueweight(g/100g)
Fastingglucose(mmol/L).
Insulin(mol/L):.
,22,45273of14
.
W–ShamW–OVXp<
Glucagon(ng/mL).
AUC0–120(mmol/L)70814755.
Serumtriglycerides(mmol/L).
Serumcholesterol(mmol/L).
NEFA(mmol/L)
HDL-C(mmol/L)
17-estradiol(pg/mL)
17-hydroxyprogesterone(ng/mL)
hs-CRP(g/mL)52359410.
HMWadiponectin(g/mL).
Leptin(pg/mL)
Ghrelin(ng/mL).
MCP-1(ng/mL)
IL-6(pg/mL).
DataaremeanSEM;n=8foreachgroup.
(overa4-monthexperimentalperiod)andfoodintakeinovariec-
tomizedWistarfemaleratscomparedtosham-
theunpairedStudent’sttest(*denotesp<,**denotesp<).
Comparedwithsham-operatedcontrols,ovariectomizedfemaleratsexhibitedmarkedly
increasedbodyweight(+10%,p<)andvisceraladiposetissueweight(+10%,p<)
(Table1andFigure1).Insulinsensitivityofperimetrialadiposetissuemeasuredaccording
totheincorporationofglucoseintolipidswassigniflcantlydecreasedinovariectomized
femaleratscomparedtoshamcontrols(p<).Basalandinsulin-stimulatedincorpo-
rationofglucoseintoglycogenmeasuredinthesoleusmuscleasaparameterofmuscle
tissueinsulinsensitivitywassigniflcantlyreducedinovariectomizedfemaleratscompared
tocontrols(p<)(Figure2).Despiteincreasedbodyweightandimpairedinsulin
sensitivityinskeletalmuscleandvisceraladiposetissue,ovariectomizedfemaleratsex-
hibitednochangesinfastingserumglucose,AUC0-120,insulin,HMWadiponectinor
pro-inflammatoryhs-CRPincomparisonwithW-shamrats(Table1).Ontheotherhand,
serumlevelsofpro-inflammatorychemokineMCP--
tomizedratsshowedelevatedserumNEFAlevelsandtriglycerideaccumulationinskeletal
muscle,whichcouldcontributetoinsulinresistanceinthistissue(Table2).Asshown
inFigure2,ovariectomizedfemaleratsdisplayeddecreasedbasalaswellasadrenaline-
-inflammatoryMCP-1
andthedecreaseinproteinsinperimetrialadiposetissue(%,
p<):.
,22,45274of14
-stimulatedsensitivityinskeletalmuscle(A-glycogenesis)andbasaland
insulin-stimulatedsensitivityinperimetrialadiposetissue(B-lipogenesis).Basalandadrenaline-
stimulatedlipolysisfromperimetrialadiposetissue(C)inovariectomizedWistarfemaleratscom-
paredtosham-’sttest
(*denotesp<,**denotesp<).
,transport,oxidativeanddicarbonylstressin
ovariectomized(W–OVX)ratscomparedtosham-operatedcontrolrats(W–sham).
W–ShamW–OVXp<
Triglyceridesintheliver(mol/g)
Cholesterolintheliver(mol/g).
TBARSintheliver(mol/mgprot)
Triglyceridesinmuscles(mol/g)
HepaticSOD(mol/g).
HepaticGPx(mmol/L)35217237
HepaticGR(mol/L)1168108.
GSHintheliver(mol/gprotein).
GSSGintheliver(mol/gprotein)
GSH/
ALT(kat/L).
AST(kat/L)
GGT(kat/L)
DataaremeanSEM;n=8foreachgroup.

AsshowninFigure3,interscapularBATofovariectomizedfemaleratsexhibited
markedlyreducedfattyacidoxidation(72%,p<),lipogenesis(26%,p<)and
lipolysis(25%,p<)
BATwasmarkedlyreduceddespitesigniflcantlyincreasedinterscapularBAT(p<)in
ovariectomizedfemalerats.

Althoughnochangesinhepaticcholesterollevelswereobserved,ovariectomyin
femaleratsmarkedlyincreasedectopictriglycerideaccumulationintheliver(p<)
(Table2),perhapshighlightingitsinvolvementinthemenopausaldevelopmentofhep-
,therewerenodifferencesin:Thedo