丁酸提高线粒体功能，减轻氧化应激，改善脂肪肝
Butyricacidcanimprovemitochondrialfunction,alleviateoxidativestressandamelioratefattyliver
1.畜禽脂肪肝Fattyliveroflivestockandpoultry
脂肪肝问题在猪、鸡、牛、羊、鱼等各种动物中均普遍发生，成为影响动物健康和畜禽肉品质的重要因素，遗传、营养、管理、药物、毒素等均可导致脂肪肝的发生。脂肪肝的形成与脂肪代谢紊乱有关，肝细胞脂肪合成增加，氧化减少。氧化应激、NO信号通路的中断和线粒体功能障碍等被认为是加速脂肪变性和启动脂肪肝和纤维化进程的关键机制，并且线粒体损伤和氧化应激之间有着复杂的相互作用。
Fattyliverdiseasearewidellyfoundinmultipleanimals,suchaspigs,chickens,cattle,sheep,andfishetc.,hasbecomeavitalfactortoaffectanimalhealthandmeatquality,andmanyfactorssuchasgenetics,nutrition,management,drugsandtoxinsetc.arepossiblythereasonsleadtoafattyliver.Theformationoffattyliverisrelatedtoadisorderofthefatmetabolismthatthefattysynthesisoflivercellsareincreasedandtheoxidationaredecreased.Theoxidativestress,disruptionofNOsignalingpathwayandmitochondrialdysfunctionareconsideredtobethekeymechanismstoacceleratesteatosisandtriggertheprocessoffattyliverandfibrosis’.Andatthesame,therealsoaresomecomplicatedinteractionsbetweenmitochondrialdamageandoxidativestress.鸡脂肪肝示意图Fattyliverofchicken
鱼脂肪肝示意图Fattyliveroffish
2.线粒体功能障碍Mitochondrialdysfunction
线粒体有“细胞动力工厂”之称，除了为细胞提供能量，还参与细胞信号转导、分化与生长、凋亡等生命过程。作为肝细胞最重要的细胞器之一，线粒体是脂肪酸进行β-氧化和三羧酸循环、腺嘌呤核苷三磷酸（ATP）合成和活性氧（ROS）形成的主要场所。缺血缺氧、药物、毒素等都可导致线粒体功能障碍，表现为形态结构变化，ATP减少，游离氧产生过度，细胞凋亡、钙离子紊乱、mtDNA损伤等。
Mitochondriaareknownasthe\powerplant\Inadditiontosupplyingenergytocellular,mitochondriaarealsoinvolvedinarangeofprocesses,suchassignaling,cellulardifferentiationandgrowth,andcelldeath.Asoneofthemostimportantorganellesofhepatocytes,mitochondriaarethemainsiteoffattyacidβ-oxidation,tricarboxylicacidcycle,adeninenucleosidetriphosphate(ATP)synthesisandROSformation.Ischemia,hypoxia,drugs,andtoxinsetc.arethepossibiltieswouldleadtoamitochondrialdysfunction,whichwouldmanifesteaschangesofmorphologicalstructure,ATPreduction,freeoxygen’sexcessiveproduction,cellapoptosis,calciumdisorder,andmtDNAdamage,etc.肝线粒体功能障碍可引起脂肪氧化的改变。线粒体脂肪酸β氧化是脂肪代谢的限速步骤，线粒体功能障碍导致肝细胞消耗游离脂肪酸的氧化磷酸化以及β-氧化减少，合成和摄取的甘油三酯增多，从而引起脂肪肝问题。
Livermitochondriadysfunctioncausessomechangesonfatoxidation.Mitochondrialfattyacid’sβoxidationistherate-limitingstepoffatmetabolism,themitochondrialdysfunctioncausestheoxidativephosphorylationoffreefattyacidsconsumedbyhepatocytes,thedecreasingofβ-oxidation,theincreasingofthesynthesizationandingestionoftriglycerides,andthat’showthefattyliveriscaused.肝线粒体功能障碍可引起活性氧(ROS)生成和氧化应激的改变。断奶、疾病、脂肪肝问题等在细胞水平上都是细胞的氧化应激，线粒体是氧化应激的作用靶点。已有大量研究报道在脂肪肝形成过程中，伴随着ROS的大量产生，线粒体氧化损伤产物如丙二醛（MDA）累积增加，线粒体内主要抗氧化蛋白GSH、SOD2
和GPX水平显著降低，抗氧化防御体系受到破坏，出现氧化应激，并进一步降低线粒体氧化呼吸功能。
ThedysfunctionoflivermitochondriawillcauseaproductionofROSandchangeofoxidativestress.Atthecellularlevel,weaning,diseaseandfattyliverproblemsarealltheoxidativestressofcellsandmitochondriaisthetargetofoxidativestress.Alargenumberofstudieshavereportedthatintheprocessoffattyliverformation,withthemassiveproductionofROS,theaccumulationofmitochondrialoxidativedamageproductssuchasmalondialdehyde(MDA)startstoriseup,andthelevelsofthemainantioxidantproteinsGSH,SOD2andGPXinthemitochondriaaresignificantlyreduced.Theantioxidantdefensesystemisdamagedandtheoxidativestressoccurred,furtherreducingthemitochondriaoxidativerespiratoryfunction.3丁酸改善线粒体功能Butyricacidimprovesmitochondrialfunction
丁酸作为一种重要的短链脂肪酸（SCFA），具有抗炎、抗癌、抗氧化和免疫调节等作用，既能作为能量基质直接被利用，也能作为信号分子调控基因和蛋白的表达。比如通过抑制组蛋白去乙酰化酶（HDAC）或激活G蛋白偶联受体41和43，来调控线粒体基因表达，影响机体代谢活动。
Asanimportantshortchainfattyacid(SCFA),butyricacidhasthefunctionsofanti-inflammatory,anti-cancer,anti-oxidationandimmuneregulation.Butyricacidcannotonlybedirectlyusedastheenergymatrix,butalsoactasasignalmoleculetoregulategeneandproteinexpression.Forexample,byinhibitinghistonedeacetylase(HDAC)oractivatingG-protein-coupledreceptors41and43,butyricacidregulatesmitochondrialgeneexpressionandaffectsthebodymetabolicactivity.丁酸可以通过减轻炎症反应、抑制胰岛素抵抗和减弱线粒体氧化应激等机制影响非酒精性脂肪肝的发生和发展。何进田等研究发现三丁酸甘油酯营养干预子宫内发育迟缓（IUGR）仔猪，可提高肝脏抗氧化能力，保护线粒体免受损伤；显著提高IUGR仔猪肝脏琥珀酸脱氢酶（SDH）、苹果酸脱氢酶（MDH）及锰超氧化物歧化酶（Mn-SOD）的活性，从而提高肝脏线粒体功能。
PS：SDH是三羧酸循环中唯一嵌入线粒体内膜的酶MDH是一种重要的氧化还原酶Mn-SOD主要存在于线粒体基质中，作为抗氧化剂PS:SDHistheonlyenzymeembeddedintheinnermitochondrialmembraneinthetricarboxylicacidcycleMDHisanimportantoxidoreductaseMnSODismainlyexistedinthemitochondrialmatrixasanantioxidant丁酸可能通过增强肝线粒体功能缓解食源性小鼠肥胖，以及大鼠的非酒精性脂肪肝。Hatzis等研究表明，补充丁酸钠可以增强肠内褪黑素的合成，进而减弱内毒素诱导的活性氧的生成和肝脏氧化应激，从而对高脂饮食所诱导的肝脏疾病的保护作用。Mollica等也发现，丁酸盐能够通过激活AMPK/ACC通路，减少ROS生成，减弱氧化应激，调节线粒体的生物效率和功能状态，从而降低肝脏脂肪。
Theobesityinmiceandnonalcoholicfattyliverinratswouldbepossiblyalleviatedbybutyricacidthroughenhancingthefunctionperformanceoflivermitochondria.StudiesofHatzisetal.showedthatasupplementofsodiumbutyratecouldenhancethesynthesisofmelatoninintheintestine,andbywhichhavereducedtheendotoxin-inducedactiveoxygenproductionandliveroxidativestress,therebytoprotectliverdiseasesinducedbyhigh-fatdiet.Mollicaetal.alsofoundoutthatthebutyratecouldreducetheproductionofROS,weakentheoxidativestress,andregulatemitochondrialbiologicalefficiencyandfunctionalstate,byactivatingAMPK/ACCpathway,therebyreducingliverfat.线粒体基因表达出现问题对能量代谢有着长期影响，丁酸可显著上调线粒体β氧化相关基因Acc1和Cpt1α的mRNA表达,和解耦联相关的关键基因Ucp2的表达，以及线粒体自身编码的8个基因的mRNA水平的表达。
Anexpressiontroubleinthemitochondrialgenehasalong-termeffectonenergymetabolism.ThebutyricacidcansignificantlyupregulatethemRNAexpressionofmitochondrialβ-oxidationrelatedgenesAcc1andCPT1α,andtheexpressionofdecoupling-relatedkeygenesUcp2,aswellasthemRNAlevelofeightgenesencodedbymitochondriathemselves.qRT-PCRanalysisformRNAexpressionlevelsofthegenesrelatedwithmitochondrialfunctioninliver(A)ThemRNAlevelsofmitochondrialfunctionassociatedgenesACC1,CPT1αandUCP2Con,normaldiet:HF,high-fatdiet:HFB,high-fatdietwithsodiumbutyratebygavagePS：PGC1α是与机体能量代谢较为密切的转录辅助激活因子，在线粒体合成等过程中发挥重要作用。ACC1和CPT-1α是机体调控长链脂肪酸进入线粒体进行β氧化的重要酶。UCP2在线粒体中与呼吸链电子传递和能量物质ATP的产生有重要的作用。PS:PGC1αplaysanimportantroleintheprocessofmitochondrialsynthesis.Acc1andCPT1αareimportantenzymesforregulatingtheβoxidationoflongchainfattyacidsintomitochondria.
三丁酸甘油酯改善脂肪肝
