TROGLITAZONE UP-REGULATES LDL RECEPTOR ACTIVITY IN HEPG2 CELLS

The aim of this in vitro study was to investigate the effect of trogli tazone, a new oral antidiabetic agent, on LDL catabolism. HepG2 cells, which are cells from a well-differentiated cell Line of hepatoma cell s, were cultured and used to study LDL catabolism. Different concentra tions of troglitazone, all within the therapeutic range for humans, we re incubated in culture medium with I-125-labeled LDL to measure cell- associated and degraded I-125-LDL. Troglitazone increased cell-associa ted and degraded 125I-LDL by similar to 30%. We also investigated if t his effect occurred through a LDL receptor-mediated pathway or a non-L DL receptor pathway. By using dextran sulfate, a substance known to re lease bound LDL from its receptor, we found that troglitazone upregula ted LDL receptor activity by similar to 35%. In addition, we found tha t troglitazone increased the expression of the LDL receptor mRNA. The effect of troglitazone was comparable with that of a 3-hydroxy-3-methy lglutaryl coenzyme A reductase inhibitor, fluvastatin, with troglitazo ne having an upregulatory effect similar to that of fluvastatin. Insul in within human physiological concentrations also increased LDL recept or activity. We found that troglitazone and insulin had an additive ef fect on LDL catabolism. Also, the effect of troglitazone on LDL catabo lism was studied in the presence of cyclosporine, an immunosuppressant drug that reduces LDL catabolism mainly by decreasing LDL receptor ac tivity. The results showed that troglitazone can compensate for the re duced LDL receptor activity induced by cyclosporine, but that cyclospo rine had a residual effect on the action of troglitazone. Thus troglit azone enhanced LDL binding, cell association, and degradation by incre asing LDL receptor mRNA expression, with a subsequent increase in LDL receptor activity.