Low-density lipoprotein metabolism in rats treated with cyclosporine

Metabolic mechanisms underlying the observations of elevated cholesterol concentration of low-density lipoprotein (LDL) in organ-transplanted patients on long-term immunosuppressant cyclosporine therapy were explored using cyclosporine-treated rats as an experimental model. As in patients, treatment with cyclosporine induced a significant elevation of plasma cholesterol level, mainly in LDL cholesterol, with a decrease in high-density lipoprotein (HDL) cholesterol level. In an in vivo cross-over study design, differentially radioiodinated homologous LDL from donor cyclosporine-treated rats (Cyc-LDL) and excipient-only-treated control rats (Exc-LDL) were injected into recipient cyclosporine-treated rats (Cyc-rats), excipient-only--treated control rats (Exc-rats), and untreated rats (Unt-rats). From the isotope disappearance curves, the fractional catabolic rate (FCR) and production rate were calculated. The results showed that FCR and production rate were significantly reduced in Cyc-rats compared with control Exc-rats and Unt-rats. The decrease was independent of the donor LDL source. In vitro LDL ligand-receptor assays indicated a twofold higher degradation of Cyc-LDL by cultured rat fibroblasts, and hence could not account for the decreased clearance observed in vivo. These results suggest that the elevated concentrations of LDL cholesterol associated with cyclosporine treatment result not from a cyclosporine-induced modification of the LDL molecule, which could diminish its receptor-mediated clearance/catabolism, but possibly from an in vivo pharmacological property of cyclosporine such as an induced hepatic dysfunction.