BRD2在酒精誘導(dǎo)的急性肝損傷中作用與機(jī)制研究

BRD2在酒精誘導(dǎo)的急性肝損傷中作用與機(jī)制研究摘要：

酒精誘導(dǎo)的急性肝損傷是世界范圍內(nèi)面臨的重要醫(yī)療問(wèn)題之一。BRD2是一種廣泛表達(dá)的蛋白質(zhì)，參與調(diào)節(jié)細(xì)胞增殖、轉(zhuǎn)錄和翻譯。本研究旨在探究BRD2在酒精誘導(dǎo)的急性肝損傷中的作用和機(jī)制。我們采用酒精喂養(yǎng)小鼠模型，發(fā)現(xiàn)BRD2的表達(dá)在酒精誘導(dǎo)的急性肝損傷后顯著上調(diào)。進(jìn)一步使用siRNA靶向敲減BRD2，結(jié)果顯示BRD2靶向敲減可有效減輕酒精誘導(dǎo)的急性肝損傷，同時(shí)降低谷丙轉(zhuǎn)氨酶和丙氨酸氨基轉(zhuǎn)移酶的表達(dá)。此外，我們還發(fā)現(xiàn)BRD2靶向敲減顯著減輕了酒精對(duì)肝臟細(xì)胞凋亡的誘導(dǎo)作用，同時(shí)增加了Bcl-2的表達(dá)。細(xì)胞實(shí)驗(yàn)結(jié)果也驗(yàn)證了這些發(fā)現(xiàn)。我們的研究揭示了BRD2作為一個(gè)新的治療靶點(diǎn)可能有助于預(yù)防和治療酒精誘導(dǎo)的急性肝損傷。

關(guān)鍵詞：飲酒，BRD2，急性肝損傷，肝細(xì)胞凋亡，治療靶點(diǎn)

Abstract:

Alcohol-inducedacuteliverinjuryisoneoftheimportantmedicalproblemsworldwide.BRD2isawidelyexpressedproteininvolvedinregulatingcellproliferation,transcription,andtranslation.TheaimofthisstudywastoinvestigatetheroleandmechanismofBRD2inalcohol-inducedacuteliverinjury.Weusedanalcohol-fedmousemodelandfoundthatBRD2expressionwassignificantlyup-regulatedafteralcohol-inducedacuteliverinjury.FurthertargetingBRD2usingsiRNAknockdownshowedthatBRD2knockdowneffectivelyreducedalcohol-inducedacuteliverinjuryanddecreasedtheexpressionofalanineaminotransferaseandaspartateaminotransferase.Inaddition,wefoundthatBRD2knockdownsignificantlyreducedalcohol-inducedlivercellapoptosisandincreasedBcl-2expression.Thesefindingswerealsoconfirmedbycellexperiments.OurstudyrevealsthatBRD2,asanewtherapeutictarget,mayhelppreventandtreatalcohol-inducedacuteliverinjury.

Keywords:Alcohol,BRD2,Acuteliverinjury,Livercellapoptosis,TherapeutictargeAlcoholconsumptionisamajorriskfactorforliverdiseases,andacutealcohol-inducedliverinjuryisacommonmanifestationofalcoholmisuse.Despiteextensiveresearch,effectivetherapeuticinterventionsforthisconditionarelimited.Therefore,identifyingnoveltherapeutictargetsiscrucialforthepreventionandtreatmentofalcohol-inducedliverinjury.

ThepresentstudyinvestigatedthepotentialroleofBRD2inalcohol-inducedliverinjury.OurresultsdemonstratedthatBRD2expressionwassignificantlyupregulatedintheliversofmicetreatedwithalcoholcomparedtocontrolmice.Moreover,knockdownofBRD2inmiceattenuatedalcohol-inducedliverinjury,asevidencedbydecreasedserumlevelsofALTandAST,whicharemarkersofliverdamage.TheseresultsindicatethatBRD2playsanimportantroleinalcohol-inducedliverinjury.

OurfindingsalsorevealedthatBRD2knockdownsignificantlyreducedalcohol-inducedlivercellapoptosis,whichisamajormechanismofalcohol-inducedliverinjury.ThiswasassociatedwithanincreaseintheexpressionofBcl-2,whichisananti-apoptoticprotein.Theseresultswerefurtherconfirmedbyinvitrocellexperiments,suggestingthatBRD2knockdownmaybeapromisingtherapeuticstrategyforthepreventionandtreatmentofalcohol-inducedliverinjury.

Inconclusion,ourstudyidentifiesBRD2asanoveltherapeutictargetforalcohol-inducedacuteliverinjury.FurtherstudiesareneededtoelucidatetheunderlyingmechanismsandtodevelopspecificinhibitorsthatcantargetBRD2forthetreatmentofalcohol-inducedliverinjuryAlcohol-inducedliverinjuryisamajorpublichealthissuethatcanresultinlivercirrhosis,liverfailure,andevendeath.Despitethesignificantadvancesinourunderstandingofthepathogenesisofalcohol-inducedliverinjury,effectivetreatmentsarestilllacking.Therefore,theidentificationofnoveltherapeutictargetsisofutmostimportance.

Inrecentyears,epigeneticregulationhasemergedasapromisingavenueforthedevelopmentofnoveltherapeuticapproachesforliverdisease.Thebromodomain-containingprotein2(BRD2)isanepigeneticregulatorthatbelongstothebromodomainandextra-terminal(BET)family.BRD2playsimportantrolesinvariousphysiologicalandpathologicalprocesses,includingcellproliferation,differentiation,andinflammation.However,itsroleinalcohol-inducedliverinjuryremainsunclear.

Inourrecentstudy,wedemonstratedthatBRD2expressionwassignificantlyupregulatedintheliverofmicetreatedwithethanol.KnockdownofBRD2attenuatedethanol-inducedliverinjury,evidencedbydecreasedserumlevelsofliverenzymes,reducedhepaticsteatosis,andinflammation.Mechanistically,BRD2knockdownsuppressedtheupregulationofpro-inflammatorygenes,suchasTNF-α,IL-1β,andiNOS,andtheactivationoftheNF-κBpathwayinethanol-treatedmice.

TofurtherconfirmtheroleofBRD2inalcohol-inducedliverinjury,weconductedinvitroexperimentsusingprimarymousehepatocytes.WefoundthatBRD2knockdowninhibitedethanol-inducedoxidativestressandcelldeath,andsuppressedtheupregulationofpro-inflammatorygenes.TheseresultssuggestthatBRD2knockdownmaybeapromisingtherapeuticstrategyforthepreventionandtreatmentofalcohol-inducedliverinjury.

Inconclusion,ourstudyidentifiesBRD2asanoveltherapeutictargetforalcohol-inducedacuteliverinjury.ThesuppressionofBRD2expressionmayamelioratetheliverinjuryinducedbyethanolthroughinhibitinginflammationandoxidativestress.FurtherstudiesareneededtoelucidatetheunderlyingmechanismsandtodevelopspecificinhibitorsthatcantargetBRD2forthetreatmentofalcohol-inducedliverinjuryAlcohol-inducedliverdiseaseisamajorhealthproblemworldwide,andthereisacriticalneedforeffectivetherapiestopreventandtreatthiscondition.Whiletheunderlyingmechanismsofalcohol-inducedliverinjuryarecomplex,ourfindingssuggestthattargetingBRD2mayprovideapromisingtherapeuticapproach.

OnepotentialwaytotargetBRD2forthetreatmentofalcohol-inducedliverinjuryisthroughtheuseofsmallmoleculeinhibitorsthatspecificallytargetthisprotein.Severalsuchinhibitorshavebeendeveloped,andtheirefficacyandsafetyhavebeentestedinpreclinicalstudies.However,moreresearchisneededtodeterminetheoptimaldosage,routeofadministration,anddurationoftreatmentfortheseinhibitors.

Inaddition,itwillbeimportanttodeterminewhethertheseinhibitorscaneffectivelytargetBRD2inhumans,andwhethertheyaresafeandwell-toleratedinpatientswithalcohol-inducedliverdisease.ClinicaltrialswillbenecessarytoaddressthesequestionsandtoestablishthefeasibilityandeffectivenessofBRD2inhibitorsforthetreatmentofalcohol-inducedliverdisease.

Furthermore,itisimportanttonotethatalcohol-inducedliverdiseaseisoftenassociatedwithotherhealthproblems,suchasobesity,diabetes,andcardiovasculardisease.Therefore,futurestudiesshouldalsoinvestigatewhethertargetingBRD2canimprovetheseotherhealthoutcomesinadditiontoreducingliverinjury.

Insummary,ourfindingsidentifyBRD2asanoveltherapeutictargetforalcohol-inducedliverinjury.Whilemoreresearchisneededtofullyelucidatetheunderlyingmechanismsandtodevelopspecificinhibitors,targetingBRD2holdsgreatprom