Al Rayyes O, Florén C H
Department of Medicine and Wallenberg Laboratory, Malmö University Hospital, Sweden.
Diabetes. 1998 Aug;47(8):1193-8. doi: 10.2337/diab.47.8.1193.
The aim of this in vitro study was to investigate the effect of troglitazone, a new oral antidiabetic agent, on LDL catabolism. HepG2 cells, which are cells from a well-differentiated cell line of hepatoma cells, were cultured and used to study LDL catabolism. Different concentrations of troglitazone, all within the therapeutic range for humans, were incubated in culture medium with 125I-labeled LDL to measure cell-associated and degraded 125I-LDL. Troglitazone increased cell-associated and degraded 125I-LDL by approximately 30%. We also investigated if this effect occurred through a LDL receptor-mediated pathway or a non-LDL receptor pathway. By using dextran sulfate, a substance known to release bound LDL from its receptor, we found that troglitazone upregulated LDL receptor activity by approximately 35%. In addition, we found that troglitazone increased the expression of the LDL receptor mRNA. The effect of troglitazone was comparable with that of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, with troglitazone having an upregulatory effect similar to that of fluvastatin. Insulin within human physiological concentrations also increased LDL receptor activity. We found that troglitazone and insulin had an additive effect on LDL catabolism. Also, the effect of troglitazone on LDL catabolism was studied in the presence of cyclosporine, an immunosuppressant drug that reduces LDL catabolism mainly by decreasing LDL receptor activity. The results showed that troglitazone can compensate for the reduced LDL receptor activity induced by cyclosporine, but that cyclosporine had a residual effect on the action of troglitazone. Thus troglitazone enhanced LDL binding, cell association, and degradation by increasing LDL receptor mRNA expression, with a subsequent increase in LDL receptor activity.
这项体外研究的目的是探究新型口服抗糖尿病药物曲格列酮对低密度脂蛋白（LDL）分解代谢的影响。HepG2细胞是源自高分化肝癌细胞系的细胞，将其培养后用于研究LDL分解代谢。将不同浓度的曲格列酮（均在人类治疗范围内）与125I标记的LDL一起在培养基中孵育，以测量细胞相关的和降解的125I-LDL。曲格列酮使细胞相关的和降解的125I-LDL增加了约30%。我们还研究了这种作用是否通过LDL受体介导的途径或非LDL受体途径发生。通过使用硫酸葡聚糖（一种已知可从其受体释放结合的LDL的物质），我们发现曲格列酮使LDL受体活性上调了约35%。此外，我们发现曲格列酮增加了LDL受体mRNA的表达。曲格列酮的作用与3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂氟伐他汀的作用相当，曲格列酮具有与氟伐他汀相似的上调作用。人类生理浓度范围内的胰岛素也可增加LDL受体活性。我们发现曲格列酮和胰岛素对LDL分解代谢具有相加作用。此外，在存在环孢素（一种主要通过降低LDL受体活性来减少LDL分解代谢的免疫抑制药物）的情况下，研究了曲格列酮对LDL分解代谢的作用。结果表明，曲格列酮可以补偿环孢素诱导的LDL受体活性降低，但环孢素对曲格列酮的作用有残余影响。因此，曲格列酮通过增加LDL受体mRNA表达来增强LDL结合、细胞摄取和降解，随后LDL受体活性增加。
