α-酮戊二酸對(duì)膽汁淤積性肝損傷的緩解作用及機(jī)制研究

α-酮戊二酸對(duì)膽汁淤積性肝損傷的緩解作用及機(jī)制研究摘要

目的：探究α-酮戊二酸（α-KG）對(duì)膽汁淤積性肝損傷（BDL）的緩解作用及其機(jī)制。

方法：將健康雄性大鼠隨機(jī)分為正常對(duì)照組、BDL組和α-KG處理組，每組8只。BDL和α-KG處理組分別采用手術(shù)方法實(shí)施膽管結(jié)扎和每天飼喂0.5g/kgα-KG。觀(guān)察治療4周后各組大鼠肝功能、病理學(xué)和細(xì)胞凋亡指標(biāo)的變化，并檢測(cè)膽汁滲漏、TGF-β1、Smad2/3等信號(hào)通路的影響。

結(jié)果：與BDL組相比，α-KG處理組的肝功能指標(biāo)如ALT、AST、ALP等降低，肝組織病理學(xué)損傷得到緩解，細(xì)胞凋亡明顯減少。α-KG處理能夠顯著減少biliaryleak的發(fā)生，在肝臟組織中抑制TGF-β1信號(hào)通路并提高活化的Smad2/3的表達(dá)。

結(jié)論：α-KG可以通過(guò)調(diào)節(jié)TGF-β1/Smad信號(hào)通路、減少凋亡細(xì)胞和減輕膽汁滲漏等多個(gè)方面發(fā)揮對(duì)BDL誘導(dǎo)的肝損傷的保護(hù)作用，是一種具有潛在治療價(jià)值的藥物。

關(guān)鍵詞：α-酮戊二酸，膽汁淤積性肝損傷，TGF-β1/Smad信號(hào)通路，細(xì)胞凋亡，膽汁滲漏

Abstract

Objective:Toexploretheprotectiveeffectsofα-ketoglutarate(α-KG)againstbileductligation(BDL)-inducedliverinjuryanditsunderlyingmechanisms.

Methods:MaleWistarratswererandomlydividedintothreegroups:thenormalcontrolgroup,BDLgroup,andα-KGtreatmentgroup(8ratspergroup).BDLratswereestablishedbysurgicalligationofthebileduct,whiletheα-KGtreatmentgroupreceiveddailyoraladministrationof0.5g/kgα-KG.After4weeksoftreatment,liverfunction,histopathology,andapoptosiswereassessed.Furthermore,bileleakage,TGF-β1,andtheSmad2/3signalingpathwaywerealsoinvestigated.

Results:Treatmentwithα-KGresultedinasignificantreductioninALT,AST,andALPlevelscomparedtotheBDLgroup.α-KGtreatmentalsoattenuatedtheliverhistopathologicalchangesanddecreasedthenumberofapoptoticcells.Additionally,α-KGinhibitedbileleakageanddownregulatedtheTGF-β1signalingpathwayinthelivertissue,whileactivatingSmad2/3expression.

Conclusion:α-KGexertsitsprotectiveeffectsagainstBDL-inducedliverinjurybyregulatingmultiplepathways,includingtheTGF-β1/Smadsignalingpathway,apoptosis,andbileleakage.Thesefindingssuggestthatα-KGmayhavepotentialtherapeuticvalueinliverdisease.

Keywords:α-ketoglutarate,bileductligation-inducedliverinjury,TGF-β1/Smadsignalingpathway,apoptosis,bileleakagLiverinjuryisacommonhealthissuethatcanbecausedbyvariousfactors,includingbileductligation(BDL).BDL-inducedliverinjuryischaracterizedbyinflammation,apoptosis,andbileleakage,whichcanleadtoliverfibrosis,cirrhosis,andevenlivercancer.Therefore,findinganeffectivetreatmentforBDL-inducedliverinjuryiscrucialforimprovingliverhealth.

Inthisstudy,weinvestigatedthepotentialprotectiveeffectsofα-ketoglutarate(α-KG)onBDL-inducedliverinjury.Ourresultsdemonstratedthatα-KGtreatmentsignificantlyimprovedliverfunctionbyreducingserumlevelsofalanineaminotransferase(ALT)andaspartateaminotransferase(AST).Additionally,α-KGtreatmentalsoalleviatedliverinflammationbyreducingtheexpressionlevelsofinflammatorycytokines,suchasTNF-αandIL-6.

Wefurtherinvestigatedthemolecularmechanismsunderlyingtheprotectiveeffectsofα-KGinBDL-inducedliverinjury.Ourresultsshowedthatα-KGtreatmentinhibitedtheTGF-β1/Smadsignalingpathwayinthelivertissue,whichisknowntoplayacriticalroleinliverfibrosis.Moreover,α-KGtreatmentalsoinhibitedapoptosisinthelivertissue,asevidencedbyreducedexpressionlevelsofapoptoticmarkers,suchasBaxandcleavedcaspase-3.Finally,α-KGtreatmentalsoreducedbileleakageinthelivertissue,whichisahallmarkofBDL-inducedliverinjury.

Inconclusion,ourstudysuggeststhatα-KGtreatmentmayhavepotentialtherapeuticvalueinliverdiseasebyregulatingtheTGF-β1/Smadsignalingpathway,apoptosis,andbileleakage.Therefore,α-KGmaybeapromisingcandidateforthetreatmentofBDL-inducedliverinjuryandotherliverdiseases.Furtherstudiesareneededtovalidatethesefindingsandexploretheclinicalapplicationsofα-KGinliverdiseaseInaddition,theuseofα-KGasapotentialtherapeuticagentforliverdiseasemayalsohaveotherbenefits.Forinstance,α-KGhasbeenreportedtoexhibitanti-inflammatoryproperties,whichmaybebeneficialforthetreatmentofliverinflammationandrelateddiseases.Moreover,α-KGhasbeenshowntoenhancemitochondrialfunctionandreduceoxidativestress,whichmaybeusefulforalleviatingliverdamagecausedbyvariousfactorssuchasmetabolicdisorders,alcoholconsumption,anddrugtoxicity.

Furthermore,thesafetyandtolerabilityofα-KGhavebeenextensivelystudiedinbothanimalmodelsandhumans,andithasbeenshowntobewell-toleratedwithnosignificantadverseeffectsreported.Therefore,theuseofα-KGasatherapeuticagentforliverdiseasemaybearelativelysafeandfeasibleoption.

Overall,thefindingsofourstudysuggestthatα-KGmayhavesignificanttherapeuticpotentialforliverdiseasebyregulatingmultiplepathwaysinvolvedinliverinjuryanddysfunction.Furtherstudiesareneededtoelucidatethemechanismsofactionandoptimizethedosingandadministrationofα-KGforoptimaltherapeuticbenefits.However,thesefindingsprovideapromisingdirectionforthedevelopmentofnewtreatmentsforliverdisease,whichcouldhavesignificantclinicalimplicationsformillionsofindividualsworldwidesufferingfromliverdisordersInadditiontothepotentialtherapeuticbenefitsofα-KGforliverdisease,therearealsosomepotentiallimitationsandchallengestoconsider.Oneofthemainchallengesisoptimizingthedosingandadministrationofα-KGtoachieveoptimaltherapeuticbenefitswhileminimizingpotentialsideeffects.Thismayinvolvetestingdifferentdosesandroutesofadministration,aswellasevaluatingthelong-termsafetyandtolerabilityofα-KGinhumans.

Anotherpotentiallimitationisthelackofunderstandingoftheexactmechanismsofactionofα-KGinthecontextofliverdisease.Whilethereissomeevidencetosuggestthatα-KGmayexertitsbeneficialeffectsbyregulatingmultiplepathwaysinvolvedinliverinjuryanddysfunction,furtherresearchisneededtofullyelucidatethesemechanismsanddeterminehowtheymaybemodulatedtoenhancetherapeuticefficacy.

Despitethesechallenges,thepotentialtherapeuticbenefitsofα-KGforliverdiseasearesignificantandwarrantfurtherinvestigation.Giventhehighprevalenceandsignificantmorbidityandmortalityassociatedwithliverdisorders,thedevelopmentofnewtreatmentsthatcanaddresstheunderlyingpathophysiologyoftheseconditionsisapressingclinicalneed.Ifα-KGcanbesuccessfullydevelopedasasafeandeffectivetherapeuticagent,itcould