弓 劍 曉 敏

(內(nèi)蒙古師范大學(xué)生命科學(xué)與技術(shù)學(xué)院，呼和浩特010022)

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多不飽和脂肪酸代謝及其對(duì)炎癥的調(diào)節(jié)

弓 劍 曉 敏

(內(nèi)蒙古師范大學(xué)生命科學(xué)與技術(shù)學(xué)院，呼和浩特010022)

炎癥是一種機(jī)體對(duì)感染或組織損傷的保護(hù)性反應(yīng)。適度的或可控的炎癥對(duì)于入侵病原微生物的清除以及受損組織的修復(fù)是必需的，然而過(guò)度的或不可控的炎癥往往會(huì)導(dǎo)致病理性炎癥反應(yīng)發(fā)生，大大提高了各種感染性和代謝性疾病的發(fā)病風(fēng)險(xiǎn)。多不飽脂肪酸代謝生成的脂質(zhì)調(diào)控介質(zhì)對(duì)炎癥的啟動(dòng)、發(fā)展以及消退均具有重要的調(diào)節(jié)作用，了解多不和脂肪酸的代謝及其代謝產(chǎn)物對(duì)炎癥反應(yīng)的調(diào)節(jié)機(jī)制，對(duì)于通過(guò)飼糧營(yíng)養(yǎng)途徑控制疾病發(fā)生以及改善人和動(dòng)物健康具有重要的理論和現(xiàn)實(shí)意義。鑒此，本文綜述了多不飽和脂肪酸的代謝途徑，并就其代謝產(chǎn)物對(duì)炎癥反應(yīng)的調(diào)節(jié)進(jìn)行了詳細(xì)論述。

多不飽和脂肪酸；代謝；脂質(zhì)調(diào)控介質(zhì)；炎癥

多不飽和脂肪酸(polyunsaturated fatty acids，PUFA)是一類(lèi)含有2個(gè)或2個(gè)以上雙鍵的多聚不飽和脂肪酸。依據(jù)第1個(gè)雙鍵在碳鏈上位置的不同，PUFA分為n-6(ω-6)和n-3(ω-3)2類(lèi)，n-6 PUFA表示第1個(gè)雙鍵位于從甲基端開(kāi)始第6～7個(gè)碳位之間，而n-3 PUFA表示第1個(gè)雙鍵位于從甲基端開(kāi)始第3～4個(gè)碳位之間。由此，1個(gè)含18個(gè)碳、2個(gè)雙鍵、第1個(gè)雙鍵位于從甲基端開(kāi)始第6～7個(gè)碳位之間的脂肪酸可表示為C18∶2n-6。大量研究證據(jù)表明，飼糧中PUFA的組成及含量會(huì)影響細(xì)胞膜磷脂中PUFA的組成和含量，而細(xì)胞膜磷脂中PUFA組成和含量的改變會(huì)影響細(xì)胞膜的流動(dòng)性以及膜受體的功能進(jìn)而影響炎癥反應(yīng)[1-2]。此外，PUFA在一定條件下可從細(xì)胞膜磷脂池中釋放出來(lái)并轉(zhuǎn)變?yōu)橛坞x狀態(tài)，游離狀態(tài)的PUFA可代謝生成上百種脂質(zhì)調(diào)節(jié)物質(zhì)，這些物質(zhì)對(duì)炎癥的啟動(dòng)、發(fā)展以及消退具有重要的調(diào)節(jié)作用[3]。絕大多數(shù)由n-6 PUFA代謝產(chǎn)生的脂質(zhì)調(diào)控介質(zhì)具有觸發(fā)炎癥反應(yīng)的作用，如果不能及時(shí)控制，往往會(huì)導(dǎo)致病理性炎癥反應(yīng)的發(fā)生，而由n-3 PUFA代謝產(chǎn)生的脂質(zhì)調(diào)節(jié)物質(zhì)具有抗炎作用或相比n-6 PUFA代謝產(chǎn)物有較低的促炎作用[4-5]，而且n-3 PUFA與n-6 PUFA利用共同的酶系進(jìn)行代謝，因而可競(jìng)爭(zhēng)性地抑制n-6 PUFA的代謝，進(jìn)而降低促炎脂質(zhì)調(diào)節(jié)物質(zhì)的產(chǎn)生；此外，n-3 PUFA還會(huì)代謝生成一些具有炎癥消退功能的脂質(zhì)調(diào)節(jié)物質(zhì)[6]。盡管PUFA代謝生成的脂質(zhì)調(diào)控介質(zhì)對(duì)炎癥的啟動(dòng)、發(fā)展以及消退均具有重要的調(diào)節(jié)作用，但調(diào)節(jié)的機(jī)理尚不清楚，而且不同的代謝產(chǎn)物對(duì)炎癥的調(diào)節(jié)作用不盡相同，甚至相同的代謝產(chǎn)物在炎癥發(fā)展的不同階段對(duì)炎癥的調(diào)節(jié)也不盡相同。本文就PUFA代謝以及代謝產(chǎn)物對(duì)炎癥反應(yīng)可能的調(diào)節(jié)機(jī)理進(jìn)行綜述，以期為通過(guò)飼糧營(yíng)養(yǎng)途徑控制疾病發(fā)生以及改善人和動(dòng)物健康提供理論依據(jù)。

1 n-6 PUFA代謝及其產(chǎn)物對(duì)炎癥反應(yīng)的調(diào)節(jié)

1.1 花生四烯酸(arachidonic acid，ARA)和亞油酸(linoleic acid，LA)代謝

ARA是n-6 PUFA的典型代表，屬于二十碳四烯酸(C20∶4n-6)。從細(xì)胞膜磷脂池中釋放出來(lái)的游離ARA主要通過(guò)酶和非酶2條途徑氧化代謝并生成具有生物活性的脂質(zhì)代謝產(chǎn)物[7]。如圖1所示，ARA在環(huán)氧合酶(cyclooxygenase，COX)的催化下生成2系列的前列腺素(prostaglandin，PG)和血栓素(thromboxane，TX)A2；在脂氧合酶(lipoxygenase，LOX)的催化下生成4系列的白三烯(leukotriene，LT)、過(guò)氧羥基二十碳四烯酸(hydroperoxyeicosatetraenoic acid，HPETE)、羥基二十碳四烯酸(hydroxyeicosatetraenoic acid，HETE)和氧代二十碳四烯酸(oxoeicosatetraenoic acid，oxo-ETE)，其中，15-HETE也可轉(zhuǎn)變?yōu)橹跛?lipoxin，LX)[8]；此外，活性氧(reactive oxygen species，ROS)可直接氧化ARA生成9-HPETE和11-HPETE，二者進(jìn)一步代謝生成9-HETE和11-HETE[9]。

LA也屬于n-6 PUFA，是ARA合成的前體，除了合成ARA外，也可通過(guò)COX和LOX途徑代謝(圖1)，生成的產(chǎn)物主要為過(guò)氧羥基十八碳二烯酸(hydroperoxyoctadecadienoic acid，HPODE)、羥基十八碳二烯酸(hydroxyoctadecadienoic acid，HODE)和氧代十八碳二烯酸(oxooctadecadienoic acid，oxo-ODE)。

ARA：花生四烯酸arachidonic acid；LOX：脂氧合酶lipoxygenase；COX：環(huán)氧合酶cyclooxygenase；ROS：活性氧reactive oxygen species；HPETE：過(guò)氧羥基二十碳四烯酸hydroperoxyeicosatetraenoic acid；HETE：羥基二十碳四烯酸hydroxyeicosatetraenoic acid；PG：前列腺素prostaglandin；LT：白三烯leukotriene；oxo-ETE：氧代二十碳四烯酸oxoeicosatetraenoic acid；LX：脂氧素lipoxin；TX：血栓素thromboxane；LA：亞油酸linoleic acid；HPODE：過(guò)氧羥基十八碳二烯酸hydroperoxyoctadecadienoic acid；HODE：羥基十八碳二烯酸hydroxyoctadecadienoic acid；oxo-ODE：氧代十八碳二烯酸oxooctadecadienoic acid。

圖1 ARA和LA代謝途徑

Fig.1 The metabolic pathways of ARA and LA[8-9]

1.2 ARA和LA代謝產(chǎn)物對(duì)炎癥反應(yīng)的調(diào)節(jié)

COX有2個(gè)同分異構(gòu)體，分別為COX-1和COX-2，在絕大多數(shù)組織中，COX-1基因通常持續(xù)表達(dá)并代謝ARA生成生理水平的PG，主要為PGI2，起著維持正常生理功能和血管功能的作用；正常生理?xiàng)l件下，COX-2基因不表達(dá)，但當(dāng)組織或細(xì)胞受到病原微生物、炎癥因子或ROS的刺激時(shí)，COX-2基因的表達(dá)量明顯提高。ARA由COX-2途徑代謝生成的脂質(zhì)調(diào)節(jié)物質(zhì)主要為PGE2、PGF2α和TXB2，奶?；既榉垦讜r(shí)，牛奶中這些物質(zhì)的含量明顯提高[10-12]。PGE2、PGF2α和TXB2具有強(qiáng)有力的促炎作用，研究較多的是PGE2，其促炎作用表現(xiàn)為誘導(dǎo)發(fā)熱、提高血管壁通透性、增強(qiáng)血管舒張、引起疼痛反應(yīng)[6]、提高白介素(interleukin，IL)-6的生成以及誘導(dǎo)COX-2活化，進(jìn)而增強(qiáng)其本身的生成[13]。一些研究表明，PGE2可通過(guò)增強(qiáng)15-LOX的活性，進(jìn)而提高具有抗炎作用的LXA4的生成[14]。近年來(lái)的研究發(fā)現(xiàn)，COX-2基因表達(dá)量的提高不僅表現(xiàn)在炎癥發(fā)起階段，在炎癥消退階段其活性也明顯提高，但催化ARA生成的脂質(zhì)調(diào)節(jié)物質(zhì)不是PGE2、PGF2α和TXB2，而是PGD2以及其下游終產(chǎn)物PGJ2[15]。PGD2和PGJ2可抑制白細(xì)胞向內(nèi)皮細(xì)胞的黏附以及核因子-κB(NF-κB)的活化，進(jìn)而抑制促炎細(xì)胞因子的生成[16]。

依據(jù)對(duì)脂肪酸氧化位點(diǎn)的不同，LOX可分為5-LOX、12-LOX和15-LOX 3種，ARA經(jīng)5-LOX途徑代謝生成的終產(chǎn)物主要為4系列的LT，具有促炎作用。例如，研究較多的LTB4，其促炎作用表現(xiàn)為提高血管壁通透性、提高局部血流速度、提高白細(xì)胞趨化性遷移、誘導(dǎo)溶酶體酶釋放、增強(qiáng)吞噬細(xì)胞ROS生成、抑制淋巴細(xì)胞增殖以及激活自然殺傷細(xì)胞[5]。LTB4對(duì)促炎細(xì)胞因子的生成也具有調(diào)節(jié)作用，可增強(qiáng)腫瘤壞死因子(tumour necrosis factor，TNF)-α、IL-1、IL-6和干擾素(interferon，IFN)-γ的產(chǎn)生[6]。ARA經(jīng)15-LOX途徑代謝生成的終產(chǎn)物主要為L(zhǎng)XA4，LXA4具有很強(qiáng)的抗炎作用，可抑制粒細(xì)胞的趨化和跨膜遷移，降低血管內(nèi)皮細(xì)胞促炎細(xì)胞因子(IL-6、IL-8)[17]、L-選擇蛋白和細(xì)胞間黏附分子-1(ICAM-1)的生成[18]。奶?；既榉垦讜r(shí)，血漿[11]和乳腺組織[10]中LXA4的含量顯著降低。近年來(lái)的研究發(fā)現(xiàn)，ARA經(jīng)LOX途徑的代謝終產(chǎn)物oxo-ETE和LA的代謝終產(chǎn)物oxo-ODE具有抗炎作用。人結(jié)腸內(nèi)皮細(xì)胞的研究表明，13-oxo-ODE可激活抗炎核受體過(guò)氧化物酶體增殖物激活受體γ，進(jìn)而降低促炎細(xì)胞因子IL-8的生成[19]。然而，終產(chǎn)物oxo-ETE和oxo-ODE的上游中間代謝產(chǎn)物HPETE和HPODE具有促炎作用。例如，13-HPODE可激活血管平滑肌細(xì)胞促炎轉(zhuǎn)錄因子NF-κB[20]，15-HPETE可增強(qiáng)促炎因子ICAM-1和血管細(xì)胞黏附分子-1(VCAM-1)基因的表達(dá)[21]。HPETE和HPODE極不穩(wěn)定，進(jìn)一步代謝生成較為穩(wěn)定的HETE和HODE。在氧化應(yīng)激和炎癥(人動(dòng)脈粥樣硬化)情況下，LOX的活性明顯增強(qiáng)，HETE和HODE在組織或細(xì)胞中含量明顯提高[22-23]；而且，對(duì)奶牛的研究發(fā)現(xiàn)，患乳房炎時(shí)，奶牛血漿和乳中HETE/oxo-ETE以及HODE/oxo-ODE的值顯著提高[11]。此外，在氧化應(yīng)激條件下，一些ROS可直接氧化ARA和LA生成HPETE和HPODE，進(jìn)而增強(qiáng)促炎反應(yīng)。

2 n-3 PUFA代謝及其產(chǎn)物對(duì)炎癥反應(yīng)的調(diào)節(jié)

2.1 二十碳五烯酸(eicosapentaenoic acid，EPA)和二十二碳六烯酸(docosahexaenoic acid，DHA)代謝

EPA和DHA屬于n-3 PUFA，其生物合成的前體為α-LA，在魚(yú)油中的含量非常豐富。如圖2所示，與ARA的代謝相似，EPA也可代謝生成PG和LT，有所不同的是，EPA經(jīng)COX-2途徑生成3系列的PG，經(jīng)5-LOX途徑生成5系列的LT[6]。阿司匹林(aspirin)是一種抗菌消炎藥，可使COX-2乙?；?，乙?；腃OX-2仍具有活性，但環(huán)氧化性減弱，脂氧化性增強(qiáng)，因而可催化EPA生成E系列的消退素(resolvin E，RvE)，包括RvE1和RvE2[24]。同樣，乙?；腃OX-2也可催化DHA生成D系列的消退素(resolvin D，RvD)，包括RvD1、RvD2、RvD3、RvD4、RvD5和RvD6[25]。此外，15-LOX可直接催化DHA生成RvD和保護(hù)素D(protectin D，PD)[25]。隨后的研究發(fā)現(xiàn)，巨噬細(xì)胞中的DHA在12-LOX的催化下可生成一種叫maresin(MaR)的脂質(zhì)調(diào)節(jié)物質(zhì)[26]。

2.2 EPA和DHA代謝產(chǎn)物對(duì)炎癥反應(yīng)的調(diào)節(jié)

從促炎角度講，代謝生成的3系列的PG和5系列的LT與ARA代謝生成的2系列的PG和4系列的LT相比具有較低的促炎作用。例如，作為化學(xué)趨化劑，LTB4對(duì)中性粒細(xì)胞的趨化作用較LTB5高出10～100倍[27]。與PGE2相比，PGE3對(duì)COX-2基因表達(dá)以及IL-6生成的誘導(dǎo)作用明顯降低[13]。

從抗炎角度講，n-3 PUFA代謝生成的多數(shù)產(chǎn)物具有抗炎和炎癥消退的雙重作用。炎癥的消退不是被動(dòng)的炎癥反應(yīng)的終止，而是一個(gè)復(fù)雜的主動(dòng)程序化過(guò)程。炎癥消退大概包括3個(gè)環(huán)節(jié)：抑制或終止粒細(xì)胞的活化、趨化和遷移，抑制或降低趨化因子和促炎細(xì)胞因子的生成，促進(jìn)粒細(xì)胞的凋亡和凋亡后清除。研究表明，RvE1通過(guò)抑制中性粒細(xì)胞活化，阻止中性粒細(xì)胞跨內(nèi)皮遷移，誘發(fā)中性粒細(xì)胞凋亡，促進(jìn)炎癥部位巨噬細(xì)胞對(duì)中性粒細(xì)胞的非炎性清除[28]以及降低細(xì)胞因子IL-12的生成[29]等途徑促進(jìn)炎癥消退。同樣，RvE2可阻止中性粒細(xì)胞的趨化和跨膜遷移[30]；RvD1可改善作為屏障的上皮和內(nèi)皮細(xì)胞膜的完整性，阻止中性粒細(xì)胞的遷移[31]，抑制TNF-α和IL-8的生成[32]；RvD2可抑制TNF-α和IL-1的生成[33]。人的血細(xì)胞和神經(jīng)膠質(zhì)細(xì)胞、小鼠的腦細(xì)胞、中性粒細(xì)胞、巨噬細(xì)胞、T細(xì)胞和視網(wǎng)膜色素細(xì)胞均可產(chǎn)生PD1，在炎癥消退的各個(gè)環(huán)節(jié)，PD1均起著重要的調(diào)節(jié)作用[34]。研究表明，PD1可限制中性粒細(xì)胞浸潤(rùn)，抑制化學(xué)趨化劑和促炎細(xì)胞因子的生成，促進(jìn)巨噬細(xì)胞對(duì)凋亡中性粒細(xì)胞的吞噬[28]。MaR1是近年來(lái)發(fā)現(xiàn)的具有抗炎和促進(jìn)炎癥消退的DHA代謝產(chǎn)物，主要在巨噬細(xì)胞中產(chǎn)生。巨噬細(xì)胞有2種表型(M1和M2型)，在炎癥啟動(dòng)和發(fā)展階段，巨噬細(xì)胞主要以M1型存在，起著調(diào)節(jié)促炎細(xì)胞因子生成和吞噬病原體的功能，而在炎癥消退階段，巨噬細(xì)胞主要以M2型存在，起著促進(jìn)炎癥消退、傷口愈合和組織再生的作用[35]。研究表明，當(dāng)巨噬細(xì)胞為M2型時(shí)，MaR1的含量明顯提高[36]。MaR1干預(yù)治療可顯著限制小鼠支氣管炎癥中性粒細(xì)胞的浸潤(rùn)和促炎介質(zhì)TNF-α、IL-6和ICAM-1的生成[37]。在脂多糖誘導(dǎo)的小鼠急性肺損傷中，MaR1可抑制中性粒細(xì)胞的浸潤(rùn)和黏附，降低白細(xì)胞在肺部的聚集，下調(diào)TNF-α、IL-1α和IL-6的生成[38]。對(duì)小鼠結(jié)腸炎的研究表明，MaR1還可抑制NF-κB的活化[39]。另外，一些研究發(fā)現(xiàn)，MaR1可誘導(dǎo)巨噬細(xì)胞由經(jīng)典活化型轉(zhuǎn)變?yōu)檠装Y消退型，而且其含量的增加與轉(zhuǎn)化為炎癥消退型巨噬細(xì)胞的數(shù)量呈正相關(guān)[40]。上述研究表明，MaR1可通過(guò)限制中性粒細(xì)胞浸潤(rùn)、增強(qiáng)巨噬細(xì)胞對(duì)凋亡中性粒細(xì)胞的吞噬、下調(diào)促炎細(xì)胞因子生成和抑制NF-κB活化等途徑使炎癥消退。

EPA：二十碳五烯酸eicosapentaenoic acid；DHA：二十二碳六烯酸docosahexaenoic acid；COX：環(huán)氧合酶cyclooxygenase；LOX:脂氧合酶lipoxygenase；aspirin:阿司匹林；PG：前列腺素prostaglandin；HPETE：過(guò)氧羥基二十碳四烯酸hydroperoxyeicosatetraenoic acid；RvE：E系列消退素 E-series resolvin；HPDHA：過(guò)氧羥基二十二碳六烯酸hydroperoxydocosahexaenoic acid；RvD：D系列消退素 D-series resolvin；PD1：保護(hù)素D1 protectin D1；NPD1：神經(jīng)保護(hù)素D1 neuroprotectin D1；MaR：maresin；Aspirin-triggered D-series Resolvins：阿司匹林誘導(dǎo)型D系列消退素；D-series Resolvins：D系列消退素。

圖2 EPA和DHA代謝途徑

Fig.2 The metabolic pathways of EPA and DHA[6,24-26]

3 小 結(jié)

綜上所述，n-6 PUFA代謝產(chǎn)物主要起著誘導(dǎo)炎癥啟動(dòng)和發(fā)展的作用，而n-3 PUFA代謝產(chǎn)物起著抗炎和促進(jìn)炎癥消退的功能。臨床上，許多疾病，如動(dòng)脈粥樣硬化、肥胖癥、奶牛產(chǎn)后乳房炎和子宮炎等的發(fā)生均與PUFA代謝紊亂進(jìn)而導(dǎo)致不可控的慢性炎癥有關(guān)。生產(chǎn)實(shí)踐中，如何有效控制炎癥的發(fā)生和發(fā)展進(jìn)而降低與其相關(guān)的疾病發(fā)生，提高飼糧n-3 PUFA的比例，降低n-6 PUFA的攝入可能是最直接有效的方法；也可在飼糧中添加一些微量元素和維生素(如硒、維生素A和維生素E)以調(diào)節(jié)PUFA代謝，進(jìn)而降低促炎脂質(zhì)調(diào)控介質(zhì)的生成；此外，甚至可以將具有抗炎和炎癥消退功能的n-3 PUFA代謝產(chǎn)物作為外源性藥物直接干預(yù)炎癥的發(fā)生和發(fā)展。

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Author, GONG Jian, associate professor, E-mail: gongjian3021@sina.com

(責(zé)任編輯 菅景穎)

The Metabolism of Polyunsaturated Fatty Acids and Its Regulation to Inflammation

GONG Jian XIAO Min

(CollegeofLifeScienceandTechnology,InnerMongoliaNormalUniversity,Huhhot010022,China)

Inflammation is part of protective response to infection or tissue injury. Appropriate or controlled inflammation is necessary to eliminate invading pathogens and repair damaged tissue. However, excessive or uncontrolled inflammation contributes to a range of pathological inflammatory responses, which may result in the increased incidence of both metabolic and infectious diseases. Lipid mediators derived from polyunsaturated fatty acids have important roles in regulating the initiation, development and resolving of inflammatory responses. A better understanding of the metabolism of polyunsaturated fatty acids and its regulation to inflammation will facilitate the development of dietary nutritional strategies to control the incidence of diseases and improve human and animal health. Therefore, the metabolic pathways of polyunsaturated fatty acids and the regulatory mechanism of its metabolic products to inflammation were reviewed in this paper.[ChineseJournalofAnimalNutrition, 2017, 29(1)：1-7]

polyunsaturated fatty acids; metabolism; lipid mediators; inflammation

10.3969/j.issn.1006-267x.2017.01.001

2016-07-14

國(guó)家自然科學(xué)基金項(xiàng)目(31560644)；內(nèi)蒙古自然科學(xué)基金項(xiàng)目(2015MS0367)；引進(jìn)高層次人才科研啟動(dòng)經(jīng)費(fèi)項(xiàng)目(2015YJRC005)

弓 劍(1975—)，男，內(nèi)蒙古涼城人，副教授，博士，主要從事反芻動(dòng)物微量元素營(yíng)養(yǎng)與飼料資源開(kāi)發(fā)利用研究。E-mail： gongjian3021@sina.com

Q547；Q493.5

A

1006-267X(2017)01-0001-07