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 atherosclerosis. In previous studies, we have shown that the immunosuppressive drug cyclosporine inhibits catabolism of low-density lipoproteins (LDL) mainly by reducing the expression of LDL-receptor messenger RNA (mRNA), thus explaining the increased plasma levels of LDL cholesterol observed in patients treated with cyclosporine. In the present study, our objective was to investigate the mechanism by which glucocorticoids increase plasma levels of LDL cholesterol. We studied the catabolism of LDL in the human hepatoma cell line HepG2. Our results show that hydrocortisone at physiologically relevant concentrations inhibits LDL binding, uptake, and degradation in a dose-dependent way. Moreover, hydrocortisone also reduces the expression of LDL-receptor mRNA in a dose-dependent way. Cyclosporine also has an additive inhibitory effect on hydrocortisone in the catabolism of LDL. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin reverses the inhibitory effect of both hydrocortisone and cyclosporine. We conclude that treatment with hydrocortisone and/or cyclosporine induces increased plasma levels of LDL cholesterol because of reduced hepatic LDL receptor activity. HMG-CoA reductase inhibitors reverse this undesirable effect and thus reduce the risk of the development of atherosclerosis in patients subjected to immunosuppressive treatment.
Al Rayyes
O
O
Department of Medicine and Wallenberg Laboratory, Malmö University Hospital, Sweden.
Wallmark
A
A
Florén
C H
CH
D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007166:Immunosuppressive Agents; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D016572:Cyclosporine; D006854:Hydrocortisone