Chen Y, Sobel B E, Schneider D J
Department of Medicine, University of Vermont, 208A South Park Drive, Suite 2, Colchester, VT 05446, USA.
Nutr Metab Cardiovasc Dis. 2002 Dec;12(6):325-30.
Concentrations in blood of plasminogen activator inhibitor type 1 (PAI-1) and circulating free (non-esterified) fatty acids (FFA) are increased in diabetes and may accelerate atherosclerosis. We have shown that FFA increase expression of PAI-1 by activation of a transcription factor that binds to the repeated sequence 5'-TG(G/C) 1-2CTG-3'. This study was designed to determine whether FFA chain length, saturation, or both affect agonist properties and whether agonist properties are mediated by activated, thioesterified FFA (fatty acyl-CoA).
Human hepatoma cells were exposed to selected FFA associated with bovine serum albumin (BSA). Triacsin C (5 microM) was used to inhibit production of fatty acyl-CoA. PAI-1 was assayed by enzyme linked immunosorbent assay. Maximal induction of PAI-1 was similar with medium and long chain FFA (fold induction of PAI-1 accumulated in conditioned media compared with control: C10 = 1.8 +/- 0.1, C12 = 2.0 +/- 0.1, C14 = 2.0 +/- 0.2, C16 = 1.4 +/- 0.1, C18 = 1.6 +/- 0.1, C20 = 1.32 +/- 0.1, p < 0.005 for each compared with control). Increased unsaturation did not alter the agonist properties of FFA (fold induction with C16: 0 = 1.4 +/- 0.1, C16: 1 = 1.4 +/- 0.1; C18: 0 = 1.6 +/- 0.1, C18: 1 = 1.5 +/- 0.1, C18: 2 = 1.6 +/- 0.1, C18: 3 = 1.4 +/- 0.1 and C20: 4 = 1.3 +/- 0.1, C20: 5 = 1.4 +/- 0.1, n = 6). However, maximal effects were seen with lower concentrations of longer chain FFA. Triacsin C consistently attenuated effects of FFA.
Longer chain FFA exhibit maximal effects at lower concentrations. Augmented expression of PAI-1 is mediated by the fatty acyl-CoA derivative. These criteria identify targets for therapy designed to normalize expression of PAI-1 and retard progression of atherosclerosis in subjects with elevated concentrations of FFA in blood including those with insulin resistance.
1型纤溶酶原激活物抑制剂（PAI - 1）的血液浓度以及循环游离（非酯化）脂肪酸（FFA）在糖尿病患者中升高，可能会加速动脉粥样硬化。我们已经表明，FFA通过激活一种与重复序列5'-TG(G/C)1 - 2CTG - 3'结合的转录因子来增加PAI - 1的表达。本研究旨在确定FFA的链长、饱和度或两者是否影响激动剂特性，以及激动剂特性是否由活化的硫酯化FFA（脂肪酰辅酶A）介导。
将人肝癌细胞暴露于与牛血清白蛋白（BSA）结合的特定FFA中。使用三乙酰基辛三烯三酮（triacsin C，5 microM）抑制脂肪酰辅酶A的产生。通过酶联免疫吸附测定法检测PAI - 1。PAI - 1的最大诱导在中链和长链FFA中相似（与对照相比，条件培养基中积累的PAI - 1的诱导倍数：C10 = 1.8 ± 0.1，C12 = 2.0 ± 0.1，C14 = 2.0 ± 0.2，C16 = 1.4 ± 0.1，C18 = 1.6 ± 0.1，C20 = 1.32 ± 0.1，与对照相比，每种情况p < 0.005）。不饱和度增加并未改变FFA的激动剂特性（C16:0的诱导倍数 = 1.4 ± 0.1，C16:1 = 1.4 ± 0.1；C18:0 = 1.6 ± 0.1，C18:1 = 1.5 ± 0.1，C18:2 = 1.6 ± 0.1，C18:3 = 1.4 ± 0.1以及C20:4 = 1.3 ± 0.1，C20:5 = 1.4 ± 0.1，n = 6）。然而，较长链FFA在较低浓度时可见最大效应。Triacsin C始终减弱FFA的作用。
较长链FFA在较低浓度时表现出最大效应。PAI - 1的增强表达由脂肪酰辅酶A衍生物介导。这些标准确定了旨在使PAI - 1表达正常化并延缓血液中FFA浓度升高的受试者（包括那些有胰岛素抵抗的受试者）动脉粥样硬化进展的治疗靶点。
