Vallette G, Vanet A, Sumida C, Nunez E A
INSERM U224, Faculty of Medicine Xavier Bichat, Paris, France.
Endocrinology. 1991 Sep;129(3):1363-9. doi: 10.1210/endo-129-3-1363.
Binding of the synthetic glucocorticoid dexamethasone to the rat liver cytosol glucocorticoid receptor was inhibited by physiological concentrations of nonesterified fatty acids as a function of increasing dose, degree of unsaturation, and chain length of the fatty acid. Polyunsaturated fatty acids were the most potent inhibitors. Scatchard analysis and Line-weaver-Burk plots of the binding data revealed that both the association constants and number of binding sites decreased and that polyunsaturated fatty acids inhibition was of a mixed non-competitive type. The dissociation rate constant of [3H]dexamethasone from glucocorticoid receptors was increased by up to 10 times in the presence of docosahexaenoic acid, whereas a competitive inhibitor like the glucocorticoid antagonist RU 38486 had no effect. Moreover, sucrose density gradient analysis showed that docosahexaenoic acid inhibited the binding of [3H] dexamethasone to both the 8.8S and 4S forms. The results strongly suggest that unsaturated fatty acids are interacting at a site on the receptor different from the hormone binding site and the heat shock protein and that by binding to a second site unsaturated fatty acids greatly change the conformation of the hormone binding site to reduce its affinity for the hormone, either partially or completely depending on the concentration and the class of the fatty acid.
合成糖皮质激素地塞米松与大鼠肝脏胞质溶胶糖皮质激素受体的结合受到生理浓度非酯化脂肪酸的抑制，这种抑制作用是脂肪酸剂量增加、不饱和度和链长的函数。多不饱和脂肪酸是最有效的抑制剂。结合数据的Scatchard分析和Line-weaver-Burk图显示，结合常数和结合位点数量均降低，且多不饱和脂肪酸的抑制作用属于混合非竞争性类型。在二十二碳六烯酸存在的情况下，[3H]地塞米松从糖皮质激素受体的解离速率常数增加了多达10倍，而糖皮质激素拮抗剂RU 38486等竞争性抑制剂则没有影响。此外，蔗糖密度梯度分析表明，二十二碳六烯酸抑制[3H]地塞米松与8.8S和4S形式的结合。结果强烈表明，不饱和脂肪酸在受体上的一个不同于激素结合位点和热休克蛋白的位点相互作用，并且通过结合到第二个位点，不饱和脂肪酸极大地改变了激素结合位点的构象，以降低其对激素的亲和力，降低程度部分或完全取决于脂肪酸的浓度和类别。
