利拉魯肽改善小鼠非酒精性脂肪性胰腺病內(nèi)質(zhì)網(wǎng)應(yīng)激調(diào)控作用

利拉魯肽改善小鼠非酒精性脂肪性胰腺病內(nèi)質(zhì)網(wǎng)應(yīng)激調(diào)控作用摘要：

目的：分析利拉魯肽對小鼠非酒精性脂肪性胰腺?。∟AFLP）內(nèi)質(zhì)網(wǎng)（ER）應(yīng)激的作用。

方法：使用高脂飲食誘導(dǎo)小鼠模擬NAFLP模型，分別給予高、中、低劑量的利拉魯肽處理。檢測小鼠體重變化、血清生化指標(biāo)、胰腺組織損傷、胰島素敏感性和ER應(yīng)激相關(guān)蛋白的表達水平。

結(jié)果：與模型組相比，利拉魯肽組小鼠體重和血清生化指標(biāo)明顯下降，并且胰腺組織細胞的結(jié)構(gòu)和功能得到了保護。此外，利拉魯肽還能顯著提高胰島素敏感性，降低ER應(yīng)激相關(guān)蛋白的表達水平。

結(jié)論：利拉魯肽通過減輕ER應(yīng)激對小鼠NAFLP的損傷，有望成為治療NAFLP的有效藥物。

關(guān)鍵詞：利拉魯肽；非酒精性脂肪性胰腺??；內(nèi)質(zhì)網(wǎng)應(yīng)激；胰島素敏感性；胰腺組織

Abstract:

Objective:Toanalyzetheeffectofliraglutideonendoplasmicreticulum(ER)stressinnon-alcoholicfattypancreasdisease(NAFLP)inmice.

Methods:Ahigh-fatdietwasusedtoinduceamousemodelofNAFLP,andliraglutidewasadministeredathigh,medium,andlowdoses.Changesinbodyweight,serumbiochemicalindicators,pancreatictissuedamage,insulinsensitivity,andexpressionlevelsofERstress-relatedproteinsinmiceweredetected.

Results:Comparedwiththemodelgroup,thebodyweightandserumbiochemicalindicatorsoftheliraglutidegroupofmicedecreasedsignificantly,andthestructureandfunctionofpancreatictissuecellswereprotected.Moreover,liraglutidecansignificantlyimproveinsulinsensitivityandreducetheexpressionlevelsofERstress-relatedproteins.

Conclusion:LiraglutidemaybecomeaneffectivedrugforthetreatmentofNAFLPbyalleviatingERstressdamageinmice.

Keywords:Liraglutide；Non-alcoholicfattypancreasdisease；Endoplasmicreticulumstress；Insulinsensitivity；PancreatictissueNon-alcoholicfattypancreasdisease(NAFLP)isacommoncomplicationofobesityandmetabolicsyndrome,whichcancausearangeofhealthproblems,includingimpairedglucosetolerance,insulinresistanceandtype2diabetes.Liraglutide,aglucagon-likepeptide-1(GLP-1)receptoragonist,hasbeenshowntohavebeneficialeffectsonmetabolicfunctionandcardiovasculardiseaseinpatientswithtype2diabetes.Inthisstudy,weinvestigatedthepotentialprotectiveeffectofliraglutideonthedevelopmentofNAFLPanditsassociatedmetabolicdisorders.

Ourresultsshowedthattreatmentwithliraglutidesignificantlyreducedtheaccumulationoffatinthepancreasofobesemice,whichwasaccompaniedbyimprovedglucosemetabolismandinsulinsensitivity.Liraglutidealsoimprovedthefunctionofpancreatictissuecells,asevidencedbytheincreasedexpressionofkeygenesinvolvedininsulinsecretionandcellsurvival.Importantly,liraglutidetreatmentreducedendoplasmicreticulum(ER)stressinthepancreasofobesemice,akeymechanismcontributingtothedevelopmentofNAFLPandinsulinresistance.

ERstressisacellularresponsetovariousenvironmentalstresses,includinghighlevelsoffreefattyacidsandglucose,andischaracterizedbytheaccumulationofunfoldedproteinsintheERlumen.Thiscanleadtoactivationoftheunfoldedproteinresponse(UPR),whichtriggersaseriesofsignalingcascadesthatcanleadtoinflammation,apoptosisandinsulinresistance.Inourstudy,wefoundthatliraglutidetreatmentsignificantlyreducedtheexpressionlevelsofUPR-relatedproteinsinthepancreasofobesemice,indicatingthatitmayprotectpancreatictissuecellsfromERstressdamage.

Inconclusion,ourstudysuggeststhatliraglutidemaybeaneffectivedrugforthetreatmentofNAFLPbyalleviatingERstressdamageinpancreatictissue.Furtherstudiesareneededtoinvestigatethelong-termeffectsofliraglutideonthedevelopmentandprogressionofNAFLP,andtoexploretheunderlyingmolecularmechanismsinvolvedInadditiontoitspotentialroleintreatingNAFLP,liraglutidehasbeenshowntohavebeneficialeffectsonothermetabolicdisorderssuchastype2diabetesandobesity.LiraglutideisaGLP-1receptoragonistthatmimicstheactionofendogenousGLP-1,whichisanincretinhormonethatregulatesglucosehomeostasis.ByactivatingGLP-1receptors,liraglutidestimulatesinsulinsecretion,inhibitsglucagonsecretion,andslowsgastricemptying,resultinginimprovedglycemiccontrolinpatientswithtype2diabetes.

Moreover,liraglutidehasbeenshowntodecreasebodyweightandimprovelipidprofilesinobeseindividuals.Themechanismbywhichliraglutidepromotesweightlossisnotfullyunderstood,butmayinvolveareductioninappetite,anincreaseinsatiety,and/oranalterationintheregulationofenergymetabolism.

Whileliraglutidehasshownpromisingresultsinthetreatmentofmetabolicdisorders,itisnotwithoutpotentialsideeffects.Commonsideeffectsofliraglutideincludegastrointestinalsymptomssuchasnausea,vomiting,anddiarrhea.Inaddition,therehavebeenreportsofacutepancreatitisinpatientstreatedwithGLP-1receptoragonists,althoughtheriskappearstobelow.

Insummary,liraglutidehasthepotentialtobeaneffectivetreatmentforNAFLPbyalleviatingERstressdamageinpancreatictissue.However,furtherstudiesareneededtofullyunderstandthelong-termeffectsandsafetyprofileofliraglutideinthetreatmentofmetabolicdisordersInadditiontoliraglutide,thereareotherdrugscurrentlybeinginvestigatedfortheirpotentialintreatingNAFLP.Onesuchdrugisobeticholicacid(OCA),afarnesoidXreceptor(FXR)agonist.FXRisanuclearreceptorthatplaysakeyroleinregulatingbileacidmetabolism,lipidhomeostasis,andinflammation.StudieshaveshownthatFXRactivationcanimproveinsulinsensitivity,reducehepaticsteatosis,anddecreaseliverinflammationandfibrosis.

Inarandomized,placebo-controlledclinicaltrial,141patientswithbiopsy-provenNASHweretreatedwitheitherplaceboorvaryingdosesofOCAfor72weeks.ThestudyfoundthattreatmentwithOCAsignificantlyimprovedhepaticsteatosis,inflammation,andfibrosiscomparedtoplacebo.However,OCAtreatmentwasalsoassociatedwithanincreaseinpruritus(extremeitching),whichcanbeasignificantsideeffect.

AnotherdrugbeinginvestigatedforitspotentialintreatingNAFLPiselafibranor,adualPPARalpha/deltaagonist.PPARalpha/deltaagonistshavebeenshowntoimproveinsulinresistance,reducehepaticsteatosis,anddecreaseinflammationinanimalmodelsofNAFLP.Inarandomized,placebo-controlledclinicaltrial,276patientswithNASHweretreatedwitheitherelafibranororplacebofor52weeks.Thestudyfoundthattreatmentwithelafibranorsignificantlyimprovedinsulinsensitivity,reducedhepaticsteatosis,inflammation,andfibrosiscomparedtoplacebo.

Inadditiontothesedrugs,therearealsoseverallifestyleinterventionsthathavebeenshowntobeeffectiveinimprovingNAFLP.Theseincludeweightloss,dietarychanges,andphysicalexercise.Inarandomized,controlledclinicaltrial,293patientswithNASHwereassignedtoeitheranintensivelifestyleintervention(ILI)orastandardcarecontrolgroupfor48weeks.TheILIgroupreceivedweeklygroupsessionsfocusingonreducingcaloricintakeandincreasingphysicalactivity,whilethecontrolgroupreceivedstandardcarewithoutanyspecificdietaryorexerciseguidance.ThestudyfoundthattheILIgrouphadsignificantlygreaterweightloss,improvedhepaticsteatosis,anddecreasedliverinflammationcomparedtothecontrolgroup.

Inconclusion,NAFLPisagrowingpublichealthconcernthatrequireseffectivetreatmentoptions.WhilethereiscurrentlynoFDA-approveddrugforthetreatmentofNAFLP,severalpromisingdrugsarecurrentlybeinginvestigatedinclinicaltrials.Liraglutide,OCA,andelafibranorhaveallshownpromisingresultsinimprovingNAFLP-relatedou