脂肪组织是机体重要的构成部分,其沉积量取决于脂肪细胞的数量和大小[1]。在动物体中,不同部位(皮下、腹腔和肌内)的脂肪沉积对于动物胴体品质和肉品质具有重要影响[2]。而在人体中,过多的脂肪沉积会导致肥胖及相关代谢疾病,如2型糖尿病、高血压和脂肪肝等[3]。因此,深入解析机体脂肪沉积的调控机制对于提高动物产品品质和改善人类健康具有重要意义。
研究表明,多不饱和脂肪酸(polyunsaturated fatty acid,PUFA)对机体脂肪沉积具有重要调控作用。如ω-3 PUFA可抑制脂肪沉积[4],预防或逆转高脂肪饮食诱导的肥胖[5]。此外,越来越多研究表明,PUFA的氧化代谢产物——氧化脂质(oxylipins)在介导PUFA调控脂肪沉积过程中起着重要作用。因此,本文在介绍氧化脂质概念和生物合成的基础上,总结了氧化脂质在脂肪生成、脂肪代谢和脂肪褐色化或产热方面的调控作用及其可能作用机制,为深入了解PUFA调控机体脂肪沉积的作用机制及其应用提供参考依据。
1 氧化脂质的概念和检测方法氧化脂质是PUFA发生自动氧化,或在环氧合酶(cyclooxygenase, COX)、脂氧合酶(lipoxygenase, LOX)、细胞色素P450(cytochrome P450, CYP)的作用下生成的一系列氧化代谢产物[6]。到目前为止,已经鉴定出100多种氧化脂质[6]。在哺乳动物中,氧化脂质可分为3类:1)由C20 PUFA[花生四烯酸(arachidonic acid, ARA)、二十碳五烯酸(eicosapentaenoic acid, EPA)和二高-γ-亚麻酸(dohomo-γ-linolenic acid, DGLA)]衍生的代谢产物合成;2)由C22 PUFA[二十二碳六烯酸(docosahexaenoic acid, DHA)]衍生的代谢产物;3)由亚油酸(linoleic acid, LA)衍生的代谢产物,包括9-羟基十八碳二烯酸(9-hydroxyoctadecadi-enoic acid, 9-HODE)和13-羟基十八碳二烯酸(13-hydroxyoctadecadi-enoic acid, 13-HODE)[7]。其中,最常见的氧化脂质是由ARA衍生的类二十烷酸和LA衍生的十八碳烯酸类化合物[8]。
目前,广泛用于检测氧化脂质的方法是液相色谱-串联质谱联用(LC-MS/MS)技术,可以分析COX、LOX和CYP产生的100多种脂质代谢物[9]。LC-MS/MS技术由于样本量小、分析速度快以及能够对分析物进行多重分析[10],成为检测氧化脂质的首选方法。
2 氧化脂质的生物合成氧化脂质在血浆中的存在形式与脂肪酸类似,既能以非酯化的形式循环,也可以在甘油酯或胆固醇酯中酯化。酯化氧化脂质的前体PUFA通常以磷脂的形式储存在膜中,经磷脂酶A2(PLA2)的激活释放到胞浆中,并在胞浆中受到COX、LOX、CYP等酶的作用生成氧化脂质[6]。目前,研究广泛的几种PUFA包括ARA、DGLA、LA、EPA和DHA等。
2.1 ARAARA经过COX的酶解作用可生成2个系列的氧化脂质,分别是前列腺素(PGs)和血栓素(TXs)[11]。有报道称,前列腺素可能直接参与脂肪细胞肥大和脂肪生成[12]。同时,ARA在2种CYP亚型[羟化酶(hydroxylase)和环氧化酶(epoxygenase)]的作用下,可分别生成羟基二十碳四烯酸(HETE)[13]和环氧二十碳三烯酸(EpETrE)[14]。EpETrE又可被可溶性环氧化物水解酶(sEH)水解生成二羟基环氧-二十碳三烯酸(DiHETrE)[6]。此外,ARA还可通过LOX途径生成HETE[15],其中5-HETE、12-HETE和15-HETE是哺乳动物中最常见的HETE[16]。ARA也可不通过酶而直接自动氧化生成氧化脂质[17]。由ARA衍生的氧化脂质见图 1。
与ARA一样,DGLA可通过COX转化为PGs和TXs[18],通过LOX生成氢过氧化物[19],并通过CYP环氧化酶和sEH生成羟基二十碳二烯酸(DiHEDE)[20]。由DGLA衍生的氧化脂质见图 2。
LA可通过12-LOX和15-LOX途径生成羟基脂肪酸[21]和羟基十八碳二烯酸(HODE)[22],也可通过CYP环氧化酶的作用生成环氧化脂肪酸,环氧化脂肪酸在sEH作用下可进一步转化为二羟基脂肪酸,如9,10-二羟基十八碳烯酸(9, 10-DiHOME)和12,13-二羟基十八碳烯酸(12, 13-DiHOME)[15]。由LA衍生的氧化脂质见图 3。
DHA可通过15-LOX途径代谢生成保护素(protectins)[23],也可以通过5-LOX途径生成17-羟基二十二碳六烯酸(17-HDoHE)[24],17-HDoHE可进一步通过LOX和环氧化步骤代谢成消退素D(D-series resolvins)[25]。同时,DHA可经过CYP羟化酶的作用生成羟基脂肪酸[24]。DHA还可通过CYP环氧化酶和sEH 2种酶的先后作用,最终转化为二羟基二十碳五烯酸(DiHDPE)[26]。此外,DHA还可通过COX-2的作用生成氢过氧化物[27]。由DHA衍生的氧化脂质见图 4。
和ARA相似,EPA可通过COX途径产生PGs和TXs[25],通过COX-2途径产生消退素E(E-series resolvins)[28]。与ARA相比,EPA通常是COX亲和性较差的底物,尤其是COX-1亚型[29]。EPA可通过CYP羟化酶生成羟基二十碳五烯酸(HEPE)[30],也可通过CYP环氧化酶的作用产生环氧化物,环氧化物进一步被sEH水解为二羟基脂肪酸[26]。EPA还可通过LOX产生氢过氧化物,可进一步转化为羟基脂肪酸[31],或在5-LOX作用下生成白三烯(LTs)[32]。由EPA衍生的氧化脂质见图 5。
脂肪沉积的增加有2种途径:一是脂肪细胞数量增多,即形成新的脂肪细胞,称为脂肪生成(adipogenesis)或增生(hyperplasia)[33];二是脂肪细胞体积增大,称为肥大(hypertrophy)。脂肪细胞大小受到脂肪合成、降解及产热等脂肪代谢过程的调控[34]。最新研究表明,氧化脂质在调控脂肪生成、脂肪代谢及产热方面起着重要的调控作用[7,35-38]。
3.1 对脂肪生成的调控作用脂肪生成过程包括干细胞定向形成脂肪前体细胞,以及脂肪前体细胞进一步分化为成熟脂肪细胞,该过程受到骨成型蛋白(bone morphogenetic protein, BMP)、锌指蛋白423(zinc finger protein 423, Zfp423)、过氧化物酶体增殖物激活受体-γ(peroxysome proliferator-activated receptor γ, PPARγ)和重组人CCAAT增强子结合蛋白(CCAAT/enhancer binding protein, C/EBPα)等信号分子和转录因子的调控[33]。最新研究表明,ARA衍生的一些氧化脂质能够调控脂肪生成。ARA可经COX途径产生前列腺素I2(PGI2),PGI2可调控脂肪细胞的增生和肥大来增加脂肪量[39],但阿司匹林等COX抑制剂会破坏这种效应[40]。相反,前列腺素E2(PGE2)和前列腺素F2α(PGF2α)对脂肪生成具有抑制作用[41-42]。此外,LOX途径生成的氧化脂质白三烯B4(LTB4)和CYP途径生成的氧化脂质EpETrE能促进脂质积累,且增加成脂相关标志基因aP2的表达[43-44]。除了ARA,α-亚麻酸(ALA)经LOX途径生成的13-氧代-十八碳三烯酸(13-oxo-OTrE)可促进3T3-L1脂肪细胞中甘油三酯积累,并增加PPARγ、aP2和CEBPα的表达水平[45]。此外,有报道显示15-LOX催化LA产生的代谢物9-HODE、13-HODE能够促进PPARγ的激活[46]。
3.2 对脂肪代谢的调控作用脂肪代谢包括脂肪合成、脂肪分解和脂肪酸氧化产热等过程。研究表明,氧化脂质能够调控脂肪代谢过程。例如,ARA衍生的PGE2和PGI2可共同影响脂肪分解,外源性PGE2可以减少脂肪分解,而PGI2可以拮抗PGE2的抗脂肪分解作用[47]。同时,抑制ARA衍生物LTB4的合成能够降低激素敏感脂酶(HSL)活性,使脂肪组织中脂肪分解速率降低[48]。高脂饲粮(HFD)会导致脂肪细胞的体积增加,而饲喂含8-HEPE的HFD的小鼠,其性腺脂肪细胞减小[49]。此外,氧化脂质合成酶活性的变化也会调控脂肪代谢。例如,利用吲哚美辛抑制COX活性,则能够增强禁食条件下的脂肪分解作用[50]。CYP基因过表达能够减轻高脂饮食诱导的高脂血症和体内脂质积累[51]。总之,氧化脂质可通过调控脂肪代谢,进而影响脂肪沉积。
3.3 对脂肪组织产热的调节作用根据不同的功能,脂肪组织可分为3类:白色脂肪组织(WAT)、褐色脂肪组织(BAT)和米色脂肪(beige cell)。其中,BAT以产热的形式消耗机体内的能量,减少脂肪沉积。在冷刺激下,白色脂肪细胞可转化成褐色脂肪细胞,称为WAT褐色化,也可促进机体产热,减少脂肪沉积[52]。
在WAT褐色化和产热上的研究报道,EpETrE可促进白色脂肪干细胞的褐色化[35]。LA和ARA则抑制WAT褐色化,这种抑制作用是通过COX介导的,导致PGE2和PGF2α的合成和释放增加[53]。
在BAT激活和产热上的研究表明,LA经CYP和sEH共同作用生成的12, 13-DiHOME可激活褐色脂肪细胞中脂肪酸转运蛋白[脂肪酸转运蛋白1(FATP1)和脂肪酸转位酶(CD36)]的转运,促进脂肪酸摄取和甘油三酯消耗,进而增加产热[38]。另外,在冷刺激下,EPA经12-LOX途径生成的12-HEPE可促进BAT和骨骼肌对葡萄糖的摄取,适应机体的产热[36]。
4 氧化脂质调控脂肪沉积的可能作用机制PUFA经酶促反应生成的氧化脂质能够与核受体过氧化物酶体增殖物激活受体(PPARs)结合,或与膜G蛋白偶联受体(GPCRs)结合来发挥其对脂肪沉积的调控功能[6],如图 6所示。
PPARs作为脂肪酸及其代谢产物的天然配体,对脂肪生成和脂肪代谢、产热等方面具有重要作用。据报道,LTs家族中的LTB4可作为PPARα配体,促进脂肪细胞的成脂分化[43]。LA的代谢产物9-HODE和13-HODE可与脂肪细胞中PPARγ结合,参与脂肪生成[54]。氧化脂质还可通过GPCRs激活或抑制第二信使Ca2+和cAMP的产生,间接介导PPARs的活性。例如,LA和ARA衍生的氧化脂质PGE2和PGF2α合成和释放增加,激活与PGE2和PGF2α结合的前列腺素膜受体,由此产生持续的钙振荡,抑制PPARγ靶基因[包括解耦联蛋白1(UCP1)基因]的表达,最终抑制WAT褐色化[54]。此外,PGI2由脂肪细胞合成和分泌后,激活GPCRs触发cAMP产生,激活蛋白激酶A(PKA),进而磷酸化cAMP效应元件结合蛋白(cAMP-response element binding protein,CREB),最终促进PPARs表达[55-56]。综上表明,氧化脂质可直接或间接与核受体PPARs结合,调控脂肪生成和WAT褐色化等,进而影响脂肪沉积。
氧化脂质也可直接介导GPCRs调控脂肪沉积。冷刺激下,BAT中12-LOX的活性增加,促进EPA衍生氧化脂质12-HEPE,其通过GPCRs触发磷酸肌醇3激酶(PI3K)-哺乳动物雷帕霉素靶蛋白复合物2(mTORC2)-蛋白激酶B(AKT)信号通路的激活,使葡萄糖转运蛋白4(GLUT4)易位到质膜,进而增加骨骼肌或脂肪组织对葡萄糖的摄取,调节机体产热[36]。在寒冷刺激下,LA衍生的氧化脂质12, 13-DiHOME水平升高,激活褐色脂肪细胞中脂肪酸转运蛋白(FATP1和CD36)的表达,从而增加脂肪酸摄取和甘油三酯清除率,促进产热[38]。
5 不同饲粮对血清或脂肪组织中氧化脂质水平的影响饲粮的变化可引起动物体内氧化脂质的显著变化。如HFD可影响动物体内氧化脂质的水平。研究表明,饲喂HFD的小鼠血浆中,环氧十八碳烯酸(EpOME)的水平显著增加[9],而短期饲喂HFD的小鼠,其血浆中HEPE和环氧二十碳四烯酸(EpETE)的水平降低[57]。同时,HFD引起的肥胖可导致脂肪组织中LTB4和PGs水平的升高[58-60]。
饲粮中不同类型脂肪酸的摄入也会导致体内氧化脂质水平的变化。研究发现,从饲粮中摄入较多的ALA会导致血清中ALA、EPA和DHA衍生的氧化脂质水平升高[61],且脂肪组织中DHA衍生的氧化脂质多于EPA衍生的氧化脂质[62]。高LA水平的饲粮会引起脂肪组织中由CYP催化产生的C20~C22氧化脂质升高,其中丰度最高的氧化脂质是三羟基十八碳烯酸(TriHOME)[63]。饲粮中EPA的摄入能够降低脂肪组织中14-羟基二十二碳六烯酸(14-HDoHE)的水平[62],饲粮中添加DHA,可使血清中4-羟基二十二碳六烯酸(4-HDoHE)、环氧二十二碳五烯酸(EpDPE)和二羟基二十二碳五烯酸(DiHDPE)的水平显著升高[64]。饲粮中添加鱼油,则血清和脂肪组织中5-HEPE水平均升高[65]。总之,不同饲粮可能通过引起动物体内氧化脂质水平的变化,进而影响机体脂肪沉积。
6 小结本文综述了氧化脂质的概念、生物合成,以及氧化脂质在脂肪生成、脂肪代谢和脂肪组织褐色化与产热方面的调控作用及其可能作用机制,可为深入了解PUFA调控机体脂肪沉积的作用机制及其在调控动物产品品质和人类健康中的应用提供参考依据。但目前的研究报道多偏向于氧化脂质对脂肪生成或脂肪组织褐色化、产热的调控,而单个氧化脂质调控脂肪沉积的机制研究却鲜有报道,未来有望发掘氧化脂质调控脂肪沉积的可能机制。
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