ADDITIVE INHIBITORY EFFECT OF HYDROCORTISONE AND CYCLOSPORINE ON LOW-DENSITY-LIPOPROTEIN RECEPTOR ACTIVITY IN CULTURED HEPG2 CELLS

Both glucocorticoids and cyclosporine are used to prevent rejection in organ transplant recipients, However, long-term treatment with these drugs is known to induce hyperlipidemia and premature development of a therosclerosis. In previous studies, we have shown that the immunosupp ressive drug cyclosporine inhibits catabolism of low-density lipoprote ins (LDL) mainly by reducing the expression of LDL-receptor messenger RNA (mRNA), thus explaining the increased plasma levels of LDL cholest erol observed in patients treated with cyclosporine. In the present st udy, our objective was to investigate the mechanism by which glucocort icoids increase plasma levels of LDL cholesterol. We studied the catab olism of LDL in the human hepatoma cell line HepG2. Our results show t hat hydrocortisone at physiologically relevant concentrations inhibits LDL binding, uptake, and degradation in a dose-dependent way. Moreove r, hydrocortisone also reduces the expression of LDL-receptor mRNA in a dose-dependent way. Cyclosporine also has an additive inhibitory eff ect on hydrocortisone in the catabolism of LDL. The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin reverses the inhibitory effect of both hydrocortisone and cyclosporine, We con clude that treatment with hydrocortisone and/or cyclosporine induces i ncreased plasma levels of LDL cholesterol. because of reduced hepatic LDL receptor activity. HMG-CoA reductase inhibitors reverse this undes irable effect and thus reduce the risk of the development of atheroscl erosis in patients subjected to immunosuppressive treatment.