共轭亚油酸两种主要异构体的分离及生理功能研究
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摘要
c9，t11CLA和t10，c12CLA是共轭亚油酸最主要的两种异构体，具有多项生理功能。能防止和减轻初期癌症，降低人体内脂肪储存量，增加蛋白质的合成，提高人体的免疫能力等。研究表明，这两种异构体有不同的作用方式和机理。t10，c12CLA侧重在减脂增肌、防止肥胖、降低胆固醇、抗动脉粥样硬化及抗癌等方面，c9，t11CLA则可促进生长、提高饲料效率等。
这两种异构体的分离技术，是深入进行CLA生理活性研究的前提。尽管对CLA的功能已有很多研究，但对CLA与血管内皮损伤和不同异构体共轭亚油酸对动脉粥样硬化的影响研究报道不多。本研究采用三种方法：优化尿素包合法、冷冻结晶法和生物酶法，对共轭亚油酸两种主要异构体进行了分离研究，完成了中试生产，通过动物实验，探讨了CLA对动脉粥样硬化的影响。主要结果如下：
1、尿素包合法对共轭亚油酸两种异构体的分离结果
中试规模尿素包后的液相中得到CLA的总量为93.68％，t10，c12CLA和c9，t11CLA两种异构体的比例达到2.34：1。尿素结晶中包合CLA的总含量为68.89％，c9，t11CLA：t10，c12CLA比例达1.54：1。
2、冷冻结晶法对共轭亚油酸两种异构体的分离结果
用乙醇作溶剂，-56℃对CLA乙酯进行冷冻分离，在乙醇与CLA乙酯的比例为18：1，反应120h时固相中得到t10，c12CLA：c9，t11CLA达16.07：1产品，远高于尿素包合法，收率为5.4％。当乙醇与CLA乙酯的比例为9：1时，冷冻31h后，冷冻结晶后所得液相中c9，t11CLA比t10，c12CLA的比例为1.63：1。回收率为82.6％。因此低温冷冻分离法适于生产两种异构体比例较高且附加值高的产品。
3、酶催化酯化法对共轭亚油酸两种异构体的分离结果
用脂肪酶Lipase AY 30进行异构体分离，优化反应条件，得CLA脂肪酸部分t10，c12CLA与c9，t11CLA的比例达2.63：1；CLA乙酯部分c9，t11CLA与t10，c12CLA的最高比可达4.72：1。说明酶催化分离两种CLA异构体，是一种非常有开发前途的技术。
4、无溶剂体系酶促酯化反应合成共轭亚油酸甘油三酯的研究结果
通过酯化反应，筛选4种固定化脂肪酶催化共轭亚油酸和甘油合成共轭亚油酸油脂。其中脂肪酶Novozym 435的催化酯化反应活性最高，反应酯化率可达94.11％。采用旋转筛筐法重复利用5次酯化率仍为87.28％。Novozym 435对共轭亚油酸异构体也有一定的选择性，但效果不如Lipase AY 30。
5、共轭亚油酸对动脉粥样硬化的影响
CLA在浓度1-5μmol／L的情况下，剂量和时间依赖性地刺激体外培养的VEC细胞生存率；可以部分阻断饱和脂肪酸PA、SA对血管内皮细胞的损伤作用，提高存活率。用上述中试实验得到的不同比例c9，t11CLA和t10，c12CLA共轭亚油酸产品，饲喂动脉粥样硬化模型大鼠8周，后实验结果表明实验组TG、TC、LDL均低于模型组，HDL较模型组高，且能升高SOD活性，降低MDA水平，显示不同异构体比例的共轭亚油酸能调节血脂，抗脂质过氧化损伤，减轻对动脉内膜的毒性。在一定程度上起到预防动脉粥样硬化形成的作用。为共轭亚油酸异构体的开发提供有价值的理论依据和生产手段。
Congjugated linoleic acid (CLA) have been shown to have a varietyof biological activities to our health, in which c9, t11CLA andt10, c12CLA isomers are more important. Studies show that both isomershave different mechanisms, t10, c12CLA play a major role onanti-arteriosclerosis, immune enhancing properties, reduction in bodyfat accretion, muscle increasing and so on. c9, t11CLA play a major roleon promote growth and improve feed efficiency.
It is necessary to separate these two isomers before develop theresearch on physiologic activity of CLA isomers. Although there are anumber of researches on the function of CLA, there is few study aboutthe influence of CLA on the survival of vascular endothelial cells.However, the survival of vascular endothelial cells has close relationshipwith the development of atherosclerosis. In this article three methodswere used such as: urea including, freeze crystallization and lipasefractionation of conjugated linoleic acid isomers. The present experimentwas to investigate the possible mechanisms on atherosclerosis in rats fedwith conjugated linoleic acid isomers. The detail study was as follows:
the two isomers t10, c12CLA and c9, t11CLA were purificated withthe method of urea including. The results showed that when reaction wasfinished the purity of CLA was 93.68%, the ratio of t10, c12CLA/c9, t11CLA was 2.34:1. The purity of CLA in the urea crystal was 68.89%and the ratio of c9, t11CLA/t10, c12 CLA was 1.54:1.
The technology of separation of Congjugated linoleic acid twoisomers by freezing crystallization was investigated. In this paper weused alcohol and removed impurity by refrigerating crystal in temperatureof-56℃. When the ratio of alcohol to CLA was 18:1, the freezing timewas 120h, we got the ratio of t10, c12CLA/c9, t11CLA was 16.07:1 in thecrystal, the yield was 5.4%. When the ratio of alcohol to CLA was 9:1, the freezing time was 31h, we got the ratio of c9, t11CLA/t10, c12CLAwas 1.63:1 in the fatty liquid, the yield was 82.6%. these prove thismethod can be used for obtaining high proportion of congjugated linoleicacid isomers production.
LipaseAY30 fractionation of congjugated linoleic acid isomers wasoptimized by orthogonal test. At the optimal conditions t10, c12CLA /c9, t11CLA content in FFA was up to 2.63:1; and c9, t11CLA/t10, c12CLAcontent in ethyl ester was up to 4.72:1. Enzymatic fractionation ofcongjugated linoleic acid isomers was a very useful method.
Novozym 435 was the best among 4 lipases when glyceride wassynthesized by esterification of glycerol and conjugated linoleicacid(CLA) in no-solvent system. The esterification ratio was 94.11%After using lipase 5 times the esterification ratio was also 87.28% withgyrating sieve. This lipase had a preference for the t10, c12CLA thanc9, t11CLA.
CLA significantly increased the vascular endothelial cell number,vascular endothelial cells survival in a time- and dose-dependent mannerwhen concentration was less than 5μmol/L. Polyunsaturated FFA CLAcould partly prevent the cell death induced by PA and SA. At the end of8~(th) week after rat experiments, we carried out a detection of TC, TG, LDL,HDL, SOD, MDA. Compared with those in the hyperlipidemia moldelgroup, the levels of MDA, TC and TG in the serum of rats given CLAwere lower while the activity of SOD and HDL in the serum of rats givenCLA were increased. The CLA had an effect of slowing downatherosclerosis, the possible mechanism may be related to the decrease ofTG, TC, MDA and the increase of HDL, SOD and anti-peroxidation.
这两种异构体的分离技术，是深入进行CLA生理活性研究的前提。尽管对CLA的功能已有很多研究，但对CLA与血管内皮损伤和不同异构体共轭亚油酸对动脉粥样硬化的影响研究报道不多。本研究采用三种方法：优化尿素包合法、冷冻结晶法和生物酶法，对共轭亚油酸两种主要异构体进行了分离研究，完成了中试生产，通过动物实验，探讨了CLA对动脉粥样硬化的影响。主要结果如下：
1、尿素包合法对共轭亚油酸两种异构体的分离结果
中试规模尿素包后的液相中得到CLA的总量为93.68％，t10，c12CLA和c9，t11CLA两种异构体的比例达到2.34：1。尿素结晶中包合CLA的总含量为68.89％，c9，t11CLA：t10，c12CLA比例达1.54：1。
2、冷冻结晶法对共轭亚油酸两种异构体的分离结果
用乙醇作溶剂，-56℃对CLA乙酯进行冷冻分离，在乙醇与CLA乙酯的比例为18：1，反应120h时固相中得到t10，c12CLA：c9，t11CLA达16.07：1产品，远高于尿素包合法，收率为5.4％。当乙醇与CLA乙酯的比例为9：1时，冷冻31h后，冷冻结晶后所得液相中c9，t11CLA比t10，c12CLA的比例为1.63：1。回收率为82.6％。因此低温冷冻分离法适于生产两种异构体比例较高且附加值高的产品。
3、酶催化酯化法对共轭亚油酸两种异构体的分离结果
用脂肪酶Lipase AY 30进行异构体分离，优化反应条件，得CLA脂肪酸部分t10，c12CLA与c9，t11CLA的比例达2.63：1；CLA乙酯部分c9，t11CLA与t10，c12CLA的最高比可达4.72：1。说明酶催化分离两种CLA异构体，是一种非常有开发前途的技术。
4、无溶剂体系酶促酯化反应合成共轭亚油酸甘油三酯的研究结果
通过酯化反应，筛选4种固定化脂肪酶催化共轭亚油酸和甘油合成共轭亚油酸油脂。其中脂肪酶Novozym 435的催化酯化反应活性最高，反应酯化率可达94.11％。采用旋转筛筐法重复利用5次酯化率仍为87.28％。Novozym 435对共轭亚油酸异构体也有一定的选择性，但效果不如Lipase AY 30。
5、共轭亚油酸对动脉粥样硬化的影响
CLA在浓度1-5μmol／L的情况下，剂量和时间依赖性地刺激体外培养的VEC细胞生存率；可以部分阻断饱和脂肪酸PA、SA对血管内皮细胞的损伤作用，提高存活率。用上述中试实验得到的不同比例c9，t11CLA和t10，c12CLA共轭亚油酸产品，饲喂动脉粥样硬化模型大鼠8周，后实验结果表明实验组TG、TC、LDL均低于模型组，HDL较模型组高，且能升高SOD活性，降低MDA水平，显示不同异构体比例的共轭亚油酸能调节血脂，抗脂质过氧化损伤，减轻对动脉内膜的毒性。在一定程度上起到预防动脉粥样硬化形成的作用。为共轭亚油酸异构体的开发提供有价值的理论依据和生产手段。
Congjugated linoleic acid (CLA) have been shown to have a varietyof biological activities to our health, in which c9, t11CLA andt10, c12CLA isomers are more important. Studies show that both isomershave different mechanisms, t10, c12CLA play a major role onanti-arteriosclerosis, immune enhancing properties, reduction in bodyfat accretion, muscle increasing and so on. c9, t11CLA play a major roleon promote growth and improve feed efficiency.
It is necessary to separate these two isomers before develop theresearch on physiologic activity of CLA isomers. Although there are anumber of researches on the function of CLA, there is few study aboutthe influence of CLA on the survival of vascular endothelial cells.However, the survival of vascular endothelial cells has close relationshipwith the development of atherosclerosis. In this article three methodswere used such as: urea including, freeze crystallization and lipasefractionation of conjugated linoleic acid isomers. The present experimentwas to investigate the possible mechanisms on atherosclerosis in rats fedwith conjugated linoleic acid isomers. The detail study was as follows:
the two isomers t10, c12CLA and c9, t11CLA were purificated withthe method of urea including. The results showed that when reaction wasfinished the purity of CLA was 93.68%, the ratio of t10, c12CLA/c9, t11CLA was 2.34:1. The purity of CLA in the urea crystal was 68.89%and the ratio of c9, t11CLA/t10, c12 CLA was 1.54:1.
The technology of separation of Congjugated linoleic acid twoisomers by freezing crystallization was investigated. In this paper weused alcohol and removed impurity by refrigerating crystal in temperatureof-56℃. When the ratio of alcohol to CLA was 18:1, the freezing timewas 120h, we got the ratio of t10, c12CLA/c9, t11CLA was 16.07:1 in thecrystal, the yield was 5.4%. When the ratio of alcohol to CLA was 9:1, the freezing time was 31h, we got the ratio of c9, t11CLA/t10, c12CLAwas 1.63:1 in the fatty liquid, the yield was 82.6%. these prove thismethod can be used for obtaining high proportion of congjugated linoleicacid isomers production.
LipaseAY30 fractionation of congjugated linoleic acid isomers wasoptimized by orthogonal test. At the optimal conditions t10, c12CLA /c9, t11CLA content in FFA was up to 2.63:1; and c9, t11CLA/t10, c12CLAcontent in ethyl ester was up to 4.72:1. Enzymatic fractionation ofcongjugated linoleic acid isomers was a very useful method.
Novozym 435 was the best among 4 lipases when glyceride wassynthesized by esterification of glycerol and conjugated linoleicacid(CLA) in no-solvent system. The esterification ratio was 94.11%After using lipase 5 times the esterification ratio was also 87.28% withgyrating sieve. This lipase had a preference for the t10, c12CLA thanc9, t11CLA.
CLA significantly increased the vascular endothelial cell number,vascular endothelial cells survival in a time- and dose-dependent mannerwhen concentration was less than 5μmol/L. Polyunsaturated FFA CLAcould partly prevent the cell death induced by PA and SA. At the end of8~(th) week after rat experiments, we carried out a detection of TC, TG, LDL,HDL, SOD, MDA. Compared with those in the hyperlipidemia moldelgroup, the levels of MDA, TC and TG in the serum of rats given CLAwere lower while the activity of SOD and HDL in the serum of rats givenCLA were increased. The CLA had an effect of slowing downatherosclerosis, the possible mechanism may be related to the decrease ofTG, TC, MDA and the increase of HDL, SOD and anti-peroxidation.
引文
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