Larsen Laila N, Granlund Linda, Holmeide Anne Kristin, Skattebøl Lars, Nebb Hilde Irene, Bremer Jon
Institute of Basic Medical Sciences, Department of Biochemistry, University of Oslo, Norway.
Lipids. 2005 Jan;40(1):49-57. doi: 10.1007/s11745-005-1359-3.
FA with varying chain lengths and an alpha-methyl group and/or a sulfur in the beta-position were tested as peroxisome proliferator-activated receptor (PPAR)alpha, -delta(beta), and -gamma ligands by transient transfection in COS-1 cells using chimeric receptor expression plasmids, containing cDNAs encoding the ligand-binding domain of PPARalpha, -delta, and -gamma. For PPARalpha, an increasing activation was found with increasing chain length of the sulfur-substituted FA up to C14-S acetic acid (tetradecylthioacetic acid = TTA). The derivatives were poor, and nonsignificant, activators of PPARdelta. For PPARgamma, activation increased with increasing chain length up to C16-S acetic acid. A methyl group was introduced in the alpha-position of palmitic acid, TTA, EPA, DHA, cis9,trans11 CLA, and trans10,cis12 CLA. An increased activation of PPARalpha was obtained for the alpha-methyl derivatives compared with the unmethylated FA. This increase also resulted in increased expression of the two PPARalpha target genes acyl-CoA oxidase and liver FA-binding protein for alpha-methyl TTA, alpha-methyl EPA, and alpha-methyl DHA. Decreased or altered metabolism of these derivatives in the cells cannot be excluded. In conclusion, saturated FA with sulfur in the beta-position and increasing carbon chain length from C9-S acetic acid to C14-S acetic acid have increasing effects as activators of PPARalpha and -gamma in transfection assays. Furthermore, alpha-methyl FA derivatives of a saturated natural FA (palmitic acid), a sulfur-substituted FA (TTA), and PUFA (EPA, DHA, c9,t11 CLA, and t10,c12 CLA) are stronger PPARalpha activators than the unmethylated compounds.
通过在COS-1细胞中使用嵌合受体表达质粒进行瞬时转染，对具有不同链长、α-甲基和/或β位硫原子的脂肪酸（FA）作为过氧化物酶体增殖物激活受体（PPAR）α、-δ（β）和-γ配体进行了测试，这些嵌合受体表达质粒包含编码PPARα、-δ和-γ配体结合域的cDNA。对于PPARα，发现随着硫取代脂肪酸链长增加至C14-S乙酸（十四烷基硫代乙酸=TTA），激活作用增强。这些衍生物对PPARδ的激活作用较差且不显著。对于PPARγ，激活作用随着链长增加至C16-S乙酸而增强。在棕榈酸、TTA、二十碳五烯酸（EPA）、二十二碳六烯酸（DHA）、顺-9，反-11共轭亚油酸（CLA）和反-10，顺-12 CLA的α位引入了甲基。与未甲基化的脂肪酸相比，α-甲基衍生物对PPARα的激活作用增强。这种增强也导致了α-甲基TTA、α-甲基EPA和α-甲基DHA这两种PPARα靶基因酰基辅酶A氧化酶和肝脏脂肪酸结合蛋白的表达增加。不能排除这些衍生物在细胞中的代谢降低或改变。总之，在转染实验中，β位含硫且碳链长度从C9-S乙酸增加到C14-S乙酸的饱和脂肪酸作为PPARα和-γ的激活剂，其作用逐渐增强。此外，饱和天然脂肪酸（棕榈酸）、硫取代脂肪酸（TTA）和多不饱和脂肪酸（EPA、DHA、c9，t11 CLA和t10，c12 CLA）的α-甲基脂肪酸衍生物是比未甲基化化合物更强的PPARα激活剂。
