Short and long term in vivo effects of Cyclosporine A and Sirolimus on genes and proteins involved in lipid metabolism in Wistar rats

ObjectiveCyclosporine A (CsA) and sirolimus (SRL) are immunosuppressive agents (IA) associated with new onset diabetes after transplantation and dyslipidemia. We aim to evaluate the molecular effects of CsA (5 mg/kg/day) and SRL (1 mg/kg/day) treatment for 3 and 9 weeks on lipid metabolism, in Wistar rats.Materials/MethodsLipolysis was evaluated in isolated adipocytes, while triglycerides (TG) and non-esterified fatty acid (NEFA) were measured in serum. Gene and protein expression involved in lipid metabolism was assessed in adipose tissue and liver.ResultsCsA and SRL treatments of rats for 3 and 9 weeks increased isoproterenol-stimulated lipolysis by 5–9 fold and 4–6 fold in isolated adipocytes, respectively. While CsA increased adipocyte weight and diameter, as well as NEFA and TG levels in circulation after 9 weeks, SRL treatment caused ectopic deposition of TG in the liver after 3 weeks. Moreover, ACC1 and FAS protein expression was increased after 3 weeks (> 100%, p < 0.01), while HSL was increased after 9 weeks of CsA treatment. On the other hand, SRL decreased the expression of lipogenic genes, including ACC1 (50%, p < 0.05), lipin1 (25%, p < 0.05), PPAR-γ (42%, p < 0.05) and SCD1 (80%, p < 0.001) in adipose tissue, after 3 weeks of treatment.ConclusionThe effects of both IAs on expression of lipolytic and lipogenic genes suggest that these agents influence lipid metabolism, thus contributing to the dyslipidemia observed during immunosuppressive therapy.