α-酮戊二酸对胆汁淤积性肝损伤的缓解作用及机制研究VIP

α-酮戊二酸对胆汁淤积性肝损伤的缓解作用及机制研究摘要

目的：探究α-酮戊二酸（α-KG）对胆汁淤积性肝损伤（BDL）的缓解作用及其机制。

方法：将健康雄性大鼠随机分为正常对照组、BDL组和α-KG处理组，每组8只。BDL和α-KG处理组分别采用手术方法实施胆管结扎和每天饲喂0.5g/kgα-KG。观察治疗4周后各组大鼠肝功能、病理学和细胞凋亡指标的变化，并检测胆汁渗漏、TGF-β1、Smad2/3等信号通路的影响。

结果：与BDL组相比，α-KG处理组的肝功能指标如ALT、AST、ALP等降低，肝组织病理学损伤得到缓解，细胞凋亡明显减少。α-KG处理能够显著减少biliaryleak的发生，在肝脏组织中抑制TGF-β1信号通路并提高活化的Smad2/3的表达。

结论：α-KG可以通过调节TGF-β1/Smad信号通路、减少凋亡细胞和减轻胆汁渗漏等多个方面发挥对BDL诱导的肝损伤的保护作用，是一种具有潜在治疗价值的药物。

关键词：α-酮戊二酸，胆汁淤积性肝损伤，TGF-β1/Smad信号通路，细胞凋亡，胆汁渗漏

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