Additive inhibitory effect of hydrocortisone and cyclosporine on low-density lipoprotein receptor activity in cultured HepG2 cells

Abstract

Both glucocorticoids and cyclosporine are used to prevent widely used to prevent organ rejection in transplant recipients in combination with cyclosporine and azathioprine. Sevrejection in organ transplant recipients. However, long-term treatment with these drugs is known to induce hyperlipidemia eral clinical studies have shown that glucocorticoids or cyclosporine, or both in combination, increase the developand premature development of atherosclerosis. In previous studies, we have shown that the immunosuppressive drug ment of atherosclerosis as a result of increased levels of LDL cholesterol. [1][2][3][4][5][6][7][8] Other clinical studies have also shown that the cyclosporine inhibits catabolism of low-density lipoproteins (LDL) mainly by reducing the expression of LDL-receptor use of glucocorticoids in chronic diseases, such as rheumatoid arthritis and systemic lupus erythematosus, increases messenger RNA (mRNA), thus explaining the increased plasma levels of LDL cholesterol observed in patients treated the liability for development of atherosclerosis due to development of hyperlipidemia. 9-11with cyclosporine. In the present study, our objective was to investigate the mechanism by which glucocorticoids increase The aim of the present study was to elucidate the mechanism by which glucocorticoids (e.g., hydrocortisone) elevate plasma levels of LDL cholesterol. We studied the catabolism of LDL in the human hepatoma cell line HepG2. Our results blood levels of LDL cholesterol. Because the liver is responsible for about two thirds of the catabolism of LDL (mainly show that hydrocortisone at physiologically relevant concentrations inhibits LDL binding, uptake, and degradation in a by the LDL receptor pathway), we performed the experiments on the hepatoma cell line HepG2, a well-defined, hudose-dependent way. Moreover, hydrocortisone also reduces the expression of LDL-receptor mRNA in a dose-dependent man-derived cell line that has maintained secretory functions, such as lipoprotein secretion, as well as functional LDL way. Cyclosporine also has an additive inhibitory effect on hydrocortisone in the catabolism of LDL. The 3-hydroxy-3-receptors. 12,13 In previous studies, we showed that cyclosporine reduces methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin reverses the inhibitory effect of both hydrocorti-the uptake of LDL by HepG2 cells mainly because of decreased expression of LDL-receptor protein.14 We also found sone and cyclosporine. We conclude that treatment with hydrocortisone and/or cyclosporine induces increased plasma that the cyclosporine-induced reduction of LDL uptake can be reversed by 3-hydroxy-3 methylglutaryl coenzyme A levels of LDL cholesterol because of reduced hepatic LDL receptor activity. HMG-CoA reductase inhibitors reverse this (HMG-CoA) reductase inhibitors, 15 thus verifying earlier clinical observations. 16,17 In the present work, we studied the undesirable effect and thus reduce the risk of the development of atherosclerosis in patients subjected to immunosuppress...

Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine–based immunosuppressive regimen: incidence, risk factors, progression, and prognosis1

“…The significantly higher values of apolipoprotein CIII observed in this group were likely to produce inhibition of the activity of lipoprotein lipase to digest blood lipids, an event that is necessary for their cellular uptake (21). These effects of sirolimus on lipid clearance mechanisms may have been intensified by the actions of CsA to interfere with basic cholesterol feedback mechanisms by affecting low-density lipoprotein receptors (22), by producing cholestasis (18), or by disrupting glucose homeostasis (1).…”

Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats

“…Hepatic LDL receptors play a pivotal role in maintaining cholesterol homeostasis in various species, and defects in the LDLR gene has been identified as one of the major causes of familial hypercholesterolemia (9). Although several in vitro systems using dexamethasone or hydrocortisone showed concentration-dependent inhibition of LDLR by CS at both mRNA and protein levels (8,10), little is known about in vivo effects of CS on these receptors. Due to technical challenges we were not able to measure either binding activity or proteins of LDLR in rat liver.…”

“…Defects or mutations in the LDLR gene result in increased plasma cholesterol, leading to an increase risk of coronary heart diseases and atherosclerosis (9). Reports studying both in vitro and in vivo systems showed CS-mediated decreases in hepatic LDLR mRNA and activity, resulting in decreased binding and degradation of LDL in both humans and rats (6,8,10). Our recent microarray studies (11) as well as preliminary studies in ADX rats where animals were dosed with 50 mg/kg MPL (unpublished results) showed a significant decrease (30-40% of baseline) in hepatic LDLR mRNA expression at 2 h posttreatment, which returned to baseline at approximately 12 h.…”

Lipoprotein‐apolipoprotein changes in renal transplant recipients

“…The corticosteroids, whose effect is predominantly on VLDL, are also able to reduce the expression of mRNA of the LDL receptor in vitro in a dose-dependent manner (34). Furthermore, data obtained in vitro show that the inhibitory effect on the uptake of the LDL by the two immunosuppressors is annulled with the use of the HMG-CoA reductase inhibitors (35).…”