Louters L L, Michele D E, Pearson J D
Department of Chemistry and Biochemistry, Calvin College, Grand Rapids, MI 49546, USA.
Biochimie. 1996;78(1):39-45. doi: 10.1016/0300-9084(96)81327-7.
Histone H4 stimulates the uptake of glucose in rat adipocytes and muscle cells. However, the mechanism of this unusual activity is not known. Therefore, we have begun to investigate the mechanism by which histone H4 stimulates the glucose uptake in rat adipocytes. We report that histone H4 requires 15-20 min to achieve its maximum effect and its time course is virtually indistinguishable from the time course of insulin itself. Reduction of the concentration of insulin receptors on the surface of adipocytes, either by trypsin digestion of the receptor, or by insulin-induced down regulation of the receptor, reduced the histone H4 effect as well as the insulin effects. Also, quercetin, a bioflavenoid that inhibits the insulin receptor tyrosine kinase activity, inhibits the actions of both histone H4 and insulin. However, histone H4 activity is somewhat more resistant to these interventions than insulin activity. In contrast to the activity of insulin, histone H4 does not appear to be able to down regulate the insulin receptor, since the pretreatment of adipocytes with histone H4 did not affect the subsequent actions of either insulin or histone H4. Finally, Scatchard analysis of the binding of 125I-insulin in the presence and absence of histone H4 increases the specific binding of insulin in a concentration dependent fashion. Histone H2b, a histone that does not have insulin-like activity, does not affect insulin binding. Taken together, these data suggest that the greatest portion of the insulin-like activity of histone H4 is initiated at the insulin receptor. However, the interaction of histone H4 and the insulin receptor is more complex than a simple binding of H4 to the insulin binding site. These studies may provide additional insight into alternate mechanisms for activation of the insulin receptor.
组蛋白H4可刺激大鼠脂肪细胞和肌肉细胞摄取葡萄糖。然而，这种异常活性的机制尚不清楚。因此，我们开始研究组蛋白H4刺激大鼠脂肪细胞摄取葡萄糖的机制。我们报告称，组蛋白H4需要15 - 20分钟才能达到其最大效应，其时间进程与胰岛素本身的时间进程几乎无法区分。通过对受体进行胰蛋白酶消化或胰岛素诱导的受体下调来降低脂肪细胞表面胰岛素受体的浓度，会同时降低组蛋白H4的效应和胰岛素的效应。此外，槲皮素是一种抑制胰岛素受体酪氨酸激酶活性的生物类黄酮，它能抑制组蛋白H4和胰岛素的作用。然而，组蛋白H4的活性比胰岛素活性对这些干预措施更具抗性。与胰岛素的活性不同，组蛋白H4似乎无法下调胰岛素受体，因为用组蛋白H4预处理脂肪细胞不会影响随后胰岛素或组蛋白H4的作用。最后，在有和没有组蛋白H4存在的情况下对125I -胰岛素结合进行Scatchard分析，结果显示胰岛素的特异性结合以浓度依赖的方式增加。组蛋白H2b是一种不具有胰岛素样活性的组蛋白，它不影响胰岛素结合。综上所述，这些数据表明组蛋白H4的胰岛素样活性的最大部分是在胰岛素受体处启动的。然而，组蛋白H4与胰岛素受体的相互作用比H4简单结合到胰岛素结合位点更为复杂。这些研究可能为胰岛素受体激活的替代机制提供更多见解。
