近年来，随着物质生活水平的不断提高，人们对绿色优质畜产品的需求也日渐增强。畜禽在生长发育过程中出现的糖代谢失调会对产品品质及机体健康造成威胁，从而引起多种代谢紊乱综合征。胆碱属维生素B4，分子式是(CH3)3N(CH2)2OH，作为动物必需的水溶性营养素，通常在饲粮中以较少的游离胆碱和磷脂酰胆碱的形式存在。动物处于特殊生理时期，通常应用具有较高生物利用率的氯化胆碱平衡肝脏糖代谢，满足动物的营养需要。
胆碱能够为细胞提供能量和构件。胆碱在机体中可作为甲基供体参与甲基代谢以合成甘氨酸和丝氨酸，是磷脂酰胆碱、乙酰胆碱(ACh)和甜菜碱的前体物[1]，并与大量营养素代谢相互作用[23]。作为脂蛋白的结构成分，磷脂酰胆碱是极低密度脂蛋白合成和肝脂输出所必需的微量物质。动物机体胆碱供给不足会引起糖脂代谢缺陷，从而造成糖尿病、非酒精性脂肪性肝炎(NASH)、动脉粥样硬化等一系列疾病的产生。研究表明，饲粮中添加过瘤胃胆碱可增加围产期奶牛肝脏中极低密度脂蛋白含量，减少甘油三酯对细胞的浸润，促进肝细胞的能量代谢，在一定程度上改善了围产期奶牛能量负平衡状态，缓解代谢疾病[4]。本文主要综述了胆碱对肝脏糖代谢主要途径、糖代谢疾病和关键信号传导通路的影响，并探讨胆碱调控相关上、下游信号传导通路的机制。
1 胆碱对肝脏糖代谢的调控 1.1 对动物肝脏糖异生的调节糖异生是指动物体内非糖的简单前体物转化为葡萄糖或者糖原的过程。研究发现，奶牛饲粮中添加过瘤胃胆碱可显著提高肝脏葡萄糖转运载体2(GLUT2)表达，降低丙酮酸羧化酶(PC)表达。GLUT2是葡萄糖出入肝细胞的重要渠道，常用来反映肝脏葡萄糖代谢能力，GLUT2表达量升高极有可能是因为过瘤胃胆碱促进了奶牛围产期肝脏葡萄糖产量，改善碳水化合物的代谢[5]。因此胆碱可直接或间接通过相关信号途径促进肝脏糖异生过程，但目前仍缺少系统性的试验依据。已有研究表明，PC在肝脏糖异生和草酰乙酸生成过程中发挥重要作用，奶牛分娩前后处于能量负平衡(NEB)时，其表达通常会上调[6-7]。因此，饲粮添加过瘤胃胆碱降低PC表达可能是因为过瘤胃胆碱改善了糖代谢，促使了能量代谢平衡以减少PC的需求。
研究显示，胆碱在小鼠肝细胞非酯化脂肪酸(NEFA)环境下可作用参与糖异生的酶发生变化，如PC、胞浆磷酸烯醇式丙酮酸羧激酶(PEPCK)和葡萄糖-6-磷酸酶(G6PC)表达量的提高[8]。G6PC参与内源性葡萄糖输出最后环节，在决定糖异生最终效应和机体葡萄糖稳态上发挥重要作用。值得注意的是，G6PC在动物中既在转录上受到调控[9-10]，又在翻译后受到调控[11]，因此后续的G6PC蛋白检查是必要的。研究表明，在低含量胆碱诱导的小鼠肝癌模型中，编码G6PC、PEPCK、果糖-1，6-二磷酸酶、PC和过氧化物酶增殖物激活受体γ共激活因子-1α(PGC-1α)的基因表达下调，血清白细胞介素-6(IL-6)含量升高，并且作为针对PGC-1α和G6PC的候选microRNA，miR-23a在小鼠肝癌细胞中的表达上调，经验证，PGC-1α和G6PC是miR-23a的直接靶点[12]。microRNA通过抑制靶基因表达来调节包括新陈代谢在内的各种生物过程[13]。信号传导与活化转录因子3(STAT3)已被证明通过抑制PGC-1a、G6PC和PEPCK的表达来抑制糖异生[14]，可直接与miR-23a的启动子区域结合，增加其表达[12]。可以看出，低水平的胆碱作用于小鼠肝癌细胞使IL-6含量升高，STAT3被激活，直接提高miR-23a表达量，下调PGC-1α的mRNA表达量来抑制糖异生。
1.2 对动物肝脏葡萄糖氧化代谢和抗氧化酶的作用葡萄糖氧化代谢可通过乙酰辅酶A和烟酰胺腺嘌呤二核苷酸(NADPH)以促进脂肪酸、固醇类的合成，其中，乙酰辅酶A由丙酮酸在肝细胞线粒体中代谢生成，NADPH则是G6PC在肝细胞胞浆中脱氢的磷酸戊糖途径产生。乙酰辅酶A和NADPH分别由丙酮酸脱氢酶(PDH)和葡萄糖-6-磷酸脱氢酶(G6PDH)催化介导。
研究表明，丙酮酸脱氢酶激酶(PDK)通过磷酸化PDH降低其活性，其中丙酮酸脱氢酶激酶4(PDK4)的表达在饥饿或由葡萄糖变为脂肪酸作为能量源的条件下增加。在低水平胆碱油酸处理的肝细胞中，PDK4的表达被高度诱导[15]。猜测胆碱可能在脂肪酸环境下通过降低PDK4的活性从而抑制PDK4对PDH的抑制作用，提高PDH活性。动物体内G6PDH为X染色体连锁遗传，它的沉默和过表达都会引起动物糖代谢异常。最新研究表明，葡萄糖有关代谢酶：PDH、G6PDH、葡萄糖激酶(GK)、丙酮酸激酶(PK)、甘油醛-3-磷酸脱氢酶(GAPDH)、磷酸葡萄糖异构酶(PGI)和亚型乳酸脱氢酶B(LDH-B)的活性可通过低水平的蛋氨酸和胆碱诱导提高[16]。蛋氨酸和胆碱在调节糖代谢上存在协同作用。GK又称己糖激酶，作为第1个关键限速酶参与糖酵解第1个阶段反应，可作为靶标来观察体内血糖变化。GK激活剂可能会增加胰腺中胰岛素的分泌从而降低肝葡萄糖的输出[17]。由于LDH-B非常适合将乳酸转化为丙酮酸，LDH-B和PDH的协同上调可促进乳酸生产乙酰辅酶A，因而缺乏胆碱不会引起肝脏乳酸中毒。
非反刍动物研究已经表明，作为甲基供体的叶酸缺乏会损害肝功能，并由于氧化应激增加而引起炎症[18]。在啮齿动物中，同样是甲基供体的胆碱缺乏会导致肝脏脂肪变性、氧化应激和炎症[19]，反刍动物研究与非反刍动物研究结果[20]一致。需要关注的是，G6PDH在过氧化氢酶(CAT)和谷胱甘肽(GSH)这些抗氧化系统中具有独特作用，其产物NADPH可直接作用GSH，将其转化为还原型以发挥抗氧化特性。CAT作用过程虽不需要NADPH，但存在NADPH的结合位点，NADPH通过别构效应可与CAT结合使其保持活化状态[21]。因此，胆碱间接作用G6PDH-NADPH-GSH/CAT的水平上调有利于维持抗氧化系统功能，抑制糖氧化代谢。
1.3 对动物糖代谢疾病的作用胰岛素抵抗和糖尿病是NASH发展的主要危险因素。近年来，胰岛素抵抗研究相对颇多，本文主要阐述胆碱通过糖尿病途径影响NASH。晚期糖基化终末产物(advanced glycation end products，AGEs)是血清蛋白的非酶糖基化产物，其修饰显著影响关键蛋白靶点的结构和功能[22-23]，且与糖尿病有关[24-25]。沉默信息调节因子1(SIRT1)通过关键代谢酶的脱乙酰化和基因表达，以及转录调节因子的脱乙酰化[26]，调节糖异生等重要代谢过程[27-28]。研究表明，SIRT1活性降低与NASH的发生有关[29]。另有研究发现，低水平胆碱作用的野生型小鼠模型SIRT1和金属蛋白酶组织抑制因子3(TIMP3)的表达下降，肿瘤坏死因子-α(TNF-α)活性上升，而活性氧化物质的生成和TNF-α转移酶(TACE)活性则随着活性TNF-α的产生以及纤维原性转录物的诱导而显著提高，糖基化终末产物受体(RAGE)的表达提高，AGEs在肝星状细胞(HSCs)中诱导NADPH氧化酶2(NOX2)活化并降低SIRT1/TIMP3的表达量[30]。TIMP3是SIRT1的靶标之一[31]，同时也是TACE活性的关键调节剂和抑制剂。NOX2作为NADPH氧化酶，已被证明在肝纤维化过程的HSCs中高度表达并具有酶活性[32-33]。综合推测，降低胆碱含量可能间接上调AGEs含量，AGEs与RAGE特异性结合，在HSCs中通过NOX2诱导和下调SIRT1/TIMP3通路介导NASH的纤维化活性。SIRT1/TIMP3/TACE级联信号通路在AGEs诱导的NASH促炎和纤维化活性中发挥着中心作用。因此，通过胆碱调节TIMP3或TACE活性可能成为阻止NASH疾病进展的有效途径。
2 腺苷一磷酸激活的蛋白激酶(AMPK)、环磷酸腺苷-蛋白激酶A(cAMP-PKA)介导胆碱对肝脏糖代谢的调控 2.1 腺苷一磷酸激活的蛋白激酶α(AMPKα)AMPK是一种活性由催化亚基α支配的丝/苏氨酸蛋白激酶，可通过对靶蛋白的磷酸化来增强分解代谢通路并抑制合成代谢通路，是细胞能量代谢的开关[34]。肝脏X受体(LXRα)属于核受体，参与肝细胞碳水化合物等多种代谢过程。当上游调控因子激活LXRα时，LXRα会在转录水平上影响下游因子或相关基因，如降低PEPCK等基因的表达，从而抑制肝细胞糖异生[35-36]。固醇调节元件结合蛋白-1c(SREBP-1c)是肝细胞重要的糖代谢调节因子，参与调控肝细胞葡萄糖代谢过程[37]。GK和PEPCK是SREBP-1c的糖代谢靶基因。当SREBP-1c过表达时，肝细胞糖代谢失衡紊乱，降低肝细胞代谢功能[38]。LXRα和SREBP-1c的表达、激活、转位等过程受AMPKα的调控[39-41]。
研究表明，AMPKα可介导胆碱对肝细胞糖代谢的调控过程，胆碱促进了肝细胞AMPKα的磷酸化激活，在NEFA诱导的LO2肝细胞模型中降低了SREBP-1c和LXRα的表达量，并且在AMPKα抑制剂6-{4-[2-(1-哌啶基)乙氧基]苯基}-3-(4-吡啶基)吡唑并[1, 5-A]嘧啶二盐酸盐(BML-275)作用下，胆碱对SREBP-1c和LXRα表达的抑制仍未下降[4]。AMPKα对LXRα的表达的影响表现在通过AMPKα-LXRα-SREBP-1c通路实现肝细胞糖代谢的调控[42-43]，但有研究表明，LXRα-SREBP-1c通路在肝细胞中无需依赖AMPKα也可调控相关代谢[44]，而且肝细胞AMPKα磷酸化激活后，还可能直接抑制SREBP-1c的表达以调控下游糖代谢基因的表达[45-46]。因此，胆碱可能通过不同途径抑制LXRα和SREBP-1c的水平，进而调控下游调节因子或相关代谢关键基因的表达，推测可能的途径有AMPKα-LXRα-SREBP-1c、AMPKα- SREBP-1c、LXRα-SREBP-1c和直接抑制。此外，碳水化合物反应元件结合蛋白(ChREBP)作为介导肝脏中葡萄糖信号的转录因子，与SREBP-1c协同调节糖酵解表达，通过siRNA沉默ChREBP基因表达，会导致内源性糖酵解基因如L-丙酮酸激酶(L-PK)的表达丧失[47]。研究表明，AMPKα磷酸化激活后抑制ChREBP的表达[37]。所以AMPKα可介导胆碱对这些下游元件因子的调控来改变动物肝脏糖代谢酶的活性，以改善糖代谢。
2.2 cAMP-PKAcAMP-PKA是细胞内经典途径之一，G蛋白偶联受体将信号首先传至腺苷酸环化酶，由它控制cAMP的含量，cAMP决定PKA的活性，PKA负责很多蛋白的磷酸化，比如受体、离子通道、转录因子等，由此调节细胞内的生物活性反应和平衡[48]。
已有研究发现，环磷腺苷效应元件结合蛋白(CREB)和ChREBP能够与SIRT1启动子3的相同序列结合，存在相反作用的竞争调节，SIRT1通过CREB-ChREBP在其启动子占有率上的互换来响应营养的可获得性[49]。如图 1，表现为在禁食过程中，上调的胰高血糖素(GCG)和去甲肾上腺素导致下游第二信使环腺苷酸(cAMP)的活化，PKA活性上升，通过磷酸化导致CREB激活和ChREBP失活，然后CREB诱导SIRT1的转录表达。反之，在摄食状态下，ChREBP与SIRT1启动子结合以下调其表达。CREB转录共激活因子2(CREB regulated transcription coactivator 2，TORC2)是血糖分子水平的调节开关。禁食期间，GCG分泌增强提高cAMP的表达，可刺激TORC2活化CREB结合SIRT1[50]。
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Glucagon morepinephrine：胰高血糖素去甲肾上腺素；Nutrient availability：营养利用率；cAMP：环磷酸腺苷cyclic adenosine monophosphate；CREB：环磷腺苷效应元件结合蛋白cAMP-response element binding protein；ChREBP：碳水化合物反应元件结合蛋白carbohydrate response element binding protein；SIRT1：沉默信息调节因子1 silent information regulator 1；Fast：禁食；Fed：摄食。 图 1 CREB和ChREBP通过整合养分有效性以协调调节SIRT1表达 Fig. 1 Nutrient availability is integrated by CREB and ChREBP to coordinately regulate SIRT1 expression[49] |
从神经传递角度看，对大鼠腹腔注射胆碱，胞苷5′-二磷酸胆碱(CDP-胆碱)或磷酸胆碱可产生多种药理作用，可升高血浆GCG含量[51-52]。后续研究表明，GCG对胆碱的反应是由神经节细胞烟碱型乙酰胆碱受体(nAChR)介导的，刺激释放的肾上腺髓质儿茶酚胺和活化的α2-肾上腺素受体能够明显介导胆碱和胆碱化合物引起的血浆GCG含量升高，中枢胆碱还通过增加中枢烟碱胆碱能神经传递，进而刺激外周自主神经系统活动来提高血浆GCG含量[53]。肝细胞中存在有胰高血糖素受体(GCGR)和肾上腺素受体，因此胆碱可通过周围自主神经系统的参与来诱导GCG和肾上腺素的提高，可能与肝细胞中受体特异性结合激活下游因子以调节糖代谢。
高效的糖异生是奶牛维持足够的乳腺葡萄糖供应的主要途径[54]。奶牛处于NEB时，GCG和肾上腺素含量上升，机体为满足能量需要，也会通过激活cAMP-PKA通路生成NEFA等脂类物质，增强肝脏糖异生作用[55]。
总而言之，胆碱在细胞质基质中通过乙酰化生成ACh，通过神经途径与nAChR特异性结合，介导胆碱对GCG的提高作用，GCG作用于肝细胞上的GCGR，活化cAMP-PKA通路，激活TORC2，降低竞争性ChREBP活性，提高CREB活性，促进CREB与SIRT1结合，使得PEPCK、G6PC、PGC-1α等基因的表达上调。
3 胆碱通过IL-6、非受体型酪氨酸蛋白激酶2-信号传导与活化转录因子3(JAK2-STAT3)、磷脂酰肌醇3激酶-蛋白激酶B(PI3K-Akt)调控肝脏糖代谢 3.1 胆碱作用IL-6-JAK2-STAT3对肝脏糖异生的调控JAK信号转导和JAK-STAT途径中，由STAT蛋白传导的JAK家族成员JAK2可被瘦素、IL-6等细胞因子激活[56]。IL-6受体被激活后，作为IL-6共用的受体和信号转导子gp130通过JAK的磷酸化激活STAT转录因子，磷酸化的STAT3形成二聚体，转移至细胞核中，激活调控基因的转录活性[57]。低水平的胆碱造成的NASH模型在特异性缺失JAK2的小鼠肝脏组织中完成停止，同时也与化学致癌物的攻击下的结果[58]相一致，表明JAK2是肝脏炎症进展的必需因子，胆碱对NASH的作用依赖JAK2。促炎因子IL-6能够抑制胰岛素和瘦素的传导，从而产生胰岛素抵抗和瘦素抵抗。研究表明，多烯磷脂胆碱联合葛根素能够治疗NASH，表现为血清谷氨酸转氨酶、天冬氨酸转氨酶活性及IL-6、白细胞介素-8(IL-8)、TNF-α含量明显降低[59]。将胆碱和CDP-胆碱脑室注射与大鼠体内，血清瘦素含量明显提高[60]。运用高脂饮食大鼠脂肪肝模型灌胃给药多烯磷脂酰胆碱，肝脏组织的血清瘦素含量也发生显著上调[61]。
已知IL-6激活STAT3会抑制糖异生[62]。结合上述胆碱对糖异生的影响，胆碱会通过IL-6-JAK2-STAT3通路调控糖异生。试验发现，糖异生调控基因PGC-1α的mRNA表达上调能够促进大鼠肝细胞糖异生相应基因肝细胞核因子4α(HNF4α)与叉头框转录因子1(FoxO1)表达的有效激活[63]。FoxO1为叉头框转录因子家族中重要的成员，归类于核受体亚家族，在肝脏中可被用于葡萄糖含量的监测[64]，FoxO1被激活后能够增加G6PC和PEPCK的表达[65]。我们推测胆碱通过阻止体内如单核巨噬细胞分泌IL-6，促进瘦素传导，在肝细胞中抑制IL-6-JAK2-STAT3通路传导，降低miR-23a的表达量，上调其下游靶点PGC-1α的mRNA表达，作用FoxO1和HNF4α活性升高，FoxO1通过提高G6PC和PEPCK的活性来促进糖异生，表现为GLUT2含量上升。
3.2 胆碱作用IL-6-PI3K-Akt对肝脏抗氧化和糖酵解的调控除了JAK-STAT通路以外，IL-6还可激活磷脂酰肌醇-3-激酶(PI3K)，通过PI3K/AKT/NF-κB共同发挥抗凋亡作用[66]。蛋白激酶B(PKB)是一种丝氨酸/苏氨酸激酶，又称Akt，作为一种原癌基因，它在调控各种不同细胞功能(包括代谢、生长、增殖、存活、转录以及蛋白质合成)方面发挥重要作用，PI3K是能够激活Akt信号级联放大的因子。因此，IL-6在肝细胞中是否也会存在作用PI3K从而调节下游糖酵解和抗氧化相关蛋白分子的情况值得我们思考。
研究显示，在缺乏胆碱饮食建立的小鼠NASH模型中，超氧化物歧化酶(SOD)活性降低，丙二醇(MDA)含量急剧增加，活性氧(ROS)含量和Akt磷酸化水平明显升高，并且在肝癌细胞系HepG2中Akt磷酸化、核因子E2相关因子2(Nrf2)易位和血红素加氧-1(heme oxygenase, HO-1)的表达明显上调[67]，油酸引起肝细胞的氧化应激可以模拟体内HepG2细胞中NASH的情况[68]。Nrf2是细胞抗氧化应激的关键转录因子，在氧化应激的情况下，胞浆内的Nrf2将从Nrf2/Keap1复合体中分离出来，然后Nrf2/Keap1复合体移位到细胞核。据报道，Nrf2是PI3K/Akt活化的重要下游靶点，可导致Nrf2从细胞质转移到细胞核，从而激活ARE/HO-1途径[69-70]。引起核Nrf2与抗氧化反应元件(ARE)的结合会触发HO-1的表达[71-73]。以往的研究表明，HO-1是肝脏中与氧化应激相关的关键酶之一[74]。
低水平胆碱和油酸所创造的细胞环境模型类似，因此有利于我们进一步探究胆碱对肝脏的作用。现有研究中，胆碱可通过Nrf2通路调控鲤鱼机体抗氧化系统，降低免疫器官的氧化损伤，进而增强免疫功能[75]。在NEFA模拟奶牛围产期的小鼠LO2模型中，添加氯化胆碱可显著提高Nrf2的表达量，增强细胞的抗氧化能力，降低TNF-α的表达量[20]。结合胆碱引起的糖酵解和抗氧化酶的变化，可初步定义为胆碱抑制IL-6-PI3K-Akt通路的传导从而靶向上调Nrf2/HO-1，使得抗氧化酶系水平上升。
有报道显示，肝前体细胞中下调的胆碱可表达叉头框转录因子A2(FoxA2)，在从缺乏胆碱饮食的大鼠中分离的肝前体细胞中敲除FoxA2可以显著增加细胞增殖和有氧糖酵解，如己糖激酶2(HK2)的酶活性被上调，通过京都基因和基因组百科全书分析显示，FoxA2敲除增强了参与PI3K/Akt途径的基因的转录，并触发了下游Akt磷酸化，效应剂Ly294002阻断PI3K-Akt通路可抑制FoxA2敲低细胞中的HK2活性，有氧糖酵解和细胞增殖[76]。因此，FoxA2通过抑制PI3K/Akt/HK2调控的需氧糖酵解在肝前体细胞的增殖和抑制中起重要作用。FoxA2是FoxO1的靶基因之一，虽未见报道胆碱有关通路作用激活FoxA2，但可推测胆碱可能通过IL-6-JAK-STAT作用PGC-1α使FoxO1上调激活FoxA2，阻断了PI3K-AKT通路的传导，抑制肝脏的糖酵解。
4 胆碱激酶与胆碱在肝脏中作用MAPK和PI3K-Akt胆碱激酶通过磷酸化胆碱生成磷酸胆碱并使其进入肯尼迪(Kennedy)途径(图 2)，用于磷脂酰胆碱的合成。磷脂酶D2裂解磷脂酰胆碱产生磷脂酸[77]，磷脂酸是MAPK和PI3K/AKT生存信号通路的关键激活剂。研究发现，转化的HeLa细胞中胆碱激酶的选择性抑制同时减弱MAPK级联激活反应和PI3K/AKT信号传导，Yalcin等[78]认为可能需要在癌细胞中合并磷脂酰胆碱，以提供对癌症生存信号通路前馈放大所必需的磷脂酸。一种胆碱激酶竞争性抑制剂N-(3, 5-二甲基苯基)-2-{[5-(4-乙基苯基)-1H-1, 2, 4-三唑-3-基]硫烷基}乙酰胺(称为CK37)也有效抑制了MAPK和PI3K/Akt的信号传导，且与作用肺癌细胞的结果[79]一致。
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Choline：胆碱；Blood：血液：Nerve：神经；Phosphatidic acid：磷脂酸；Kennedy pathway：肯尼迪途径；AMPKα：腺苷一磷酸激活的蛋白激酶α adenosine monophosphate activated protein kinase α；LXRα：肝脏X受体α liver X receptor α；SREBP-1c：固醇调节元件结合蛋白-1c sterol regulatory element-binding protein-1c；CREB：环磷腺苷效应元件结合蛋白cAMP-response element binding protein；ChREBP：碳水化合物反应元件结合蛋白carbohydrate response element binding protein；ACh：乙酰胆碱acetylcholine；nAChR：烟碱型乙酰胆碱受体nicotinic acetylcholine receptor；GCG：胰高血糖素glucagon；GCGR：胰高血糖素受体glucagon receptor；cAMP：环磷酸腺苷cyclic adenosine monophosphate；PKA：蛋白激酶A protein kinase A；TORC2：CREB转录共激活因子2 CREB regulated transcription coactivator 2；AGEs：晚期糖基化终末产物advanced glycation end products；RAGE：糖基化终末产物受体advanced glycation end products receptor；NOX2：NADPH氧化酶2 nicotinamide adenine dinucleotide phosphate oxidase 2；SIRT1：沉默信息调节因子1 silent information regulator 1；TIMP3：金属蛋白酶组织抑制因子3 tissue inhibitors of metalloproteinase 3；TACE：肿瘤坏死因子α转移酶tumor necrosis factor-converting enzyme α；IL-6：白细胞介素-6 interleukin-6；JAK2：非受体型酪氨酸蛋白激酶2 janus kinase 2；STAT3：信号传导与活化转录因子3 signal transducer and activator of transcription 3；miR-23a：微RNA-23a micro RNA-23a；PGC-1α：过氧化物酶增殖物激活受体γ共激活因子-1α peroxisome proliferator-activated receptor γ coactivator-1α；FoxO1：叉形头转录因子O1 Forkhead box O1；FoxA2：叉头框转录因子A2 Forkhead box A2；PI3K：磷脂酰肌醇3激酶phosphatidylinositol 3-kinase；AKT：蛋白激酶B protein kinase B；Nrf2：核因子E2相关因子2 nuclear factor erythroid 2-related factor 2；G6PDH：葡萄糖-6-磷酸脱氢酶glucose-6-phosphate dehydrogenase；NADPH：烟酰胺腺嘌呤二核苷酸nicotinamide adenine dinucleotide phosphate；GSH：谷胱甘肽glutathione；CAT：过氧化氢酶catalase；HO-1：血红素加氧-1 heme oxygenase-1；HK2：己糖激酶2 recombinant hexokinase 2；PDK4：丙酮酸脱氢酶激酶4 pyruvate dehydrogenase kinase 4；PDH：丙酮酸脱氢酶pyruvate dehydrogenase；MAPK：丝裂原活化蛋白激酶mitogen-activated protein kinase；CNTF：睫状神经营养因子ciliary neuyotrophic factor；ChAT：胆碱乙酰基转移酶choline acetyltransferase；GK：葡萄糖激酶glucokinase；PEPCK：磷酸烯醇式丙酮酸羧激酶phosphoenolpyruvate carboxykinase；G6PC：葡萄糖-6-磷酸酶glucose-6-phosphatase；GLUT2：葡萄糖转运载体2 glucose transporter 2。 图 2 胆碱通过不同途径在脂肪肝/肝癌/NEFA细胞环境中可能的调节作用 Fig. 2 Likely regulation effects of choline in fatty liver/hepatocellular carcinoma/NEFA cell through different pathways |
HeLa宫颈癌细胞系和肺癌细胞的结果一致，猜测此作用效果在肝癌细胞也同样受用。研究显示，胆碱能够提高肝脏磷脂酰胆碱含量[80]，并且胆碱作为一碳单位循环的关键分子，会通过CDP-胆碱途径促进代谢调节[81]。胆碱处理的奶牛原代肝细胞在CDP-胆碱途径中，胆碱激酶α、胆碱激酶β、磷酸胞苷转移酶1α和胆碱/乙醇胺磷酸转移酶1的含量得到显著上调[82]。胆碱的补充可能导致更多的CDP-胆碱通过Kennedy途径合成磷脂酰胆碱[83]。胆碱通过一系列途径参与磷脂酰胆碱和磷脂酸的合成，结合Yalcin等[84]的观点，认为在作用相关下游通路中也是必不可少的。在胆碱激酶的做作用下，胆碱磷脂酸水平的上调，抑制MAPK的级联激活反应和PI3K-Akt的信号传导。睫状神经营养因子(CNTF)上调合成神经递质ACh的胆碱乙酰基转移酶(ChAT)的表达。MAPK途径的激活会抑制CNTF激活的ChAT的表达。其中，MAPK的级联激活反应是指MAPKKK-MAPKK-MAPK的级联磷酸化激活下游蛋白激酶，PI3K-Akt的作用途径由3.2可知。
5 小结通过阐述胆碱对肝脏糖代谢及代谢疾病的影响，引申至信号传导通路(图 2)，不难发现，在本文涉及到的可能存在的多个不同信号传导通路之间发生了交叉调控，形成了一定的信号传导网络。举例说明，胆碱对糖代谢疾病的影响可能通过AMPK和cAMP-PKA促进SIRT1-TIMP3-TACE级联信号通路的传导。SIRT1已被证明调节STAT3的乙酰化和磷酸化，从而抑制其对糖异生的抑制作用[85]。胆碱上调的SIRT1通过降低STAT3的乙酰化和磷酸化水平促进下游信号传导分子提高G6PC和PEPCK的活性，改善糖代谢。此外，乙酰胆碱通过神经途径特异性结合其受体，抑制JAK2-STAT3的激活，并与胆碱Kennedy途径转化的磷脂酸共同作用于PI3K-Akt和Nrf2的活化。此过程存在SIRT1的参与。磷脂酸也会抑制MAPK的级联激活以刺激神经途径发挥作用。综上所述，胆碱可能作用这些核心通路促使下游糖异生、糖氧化代谢和抗氧化等因子产生有利变化，完成肝脏糖代谢调节过程。
胆碱在肝脏中充当着重要的角色，能够一定程度上改善动物糖代谢的水平，可有效避免脂肪肝、炎症和氧化应激等代谢并发疾病的发生。总的来说，结合国内外相关研究进展，聚焦胆碱对动物肝脏糖代谢途径相关元件因子的调控作用，将多条信号传导通路进行有效整合，有利于系统地解析胆碱调控动物特殊生理阶段糖代谢的分子机制和网络，以应用于动物生产。
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