Center for Neuroscience and Cell Biology, University of Coimbra, 3000-517 Coimbra, Portugal.
Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Institute for Nuclear Sciences Applied to Heath-ICNAS, University of Coimbra, 3000-548 Coimbra, Portugal.
Metabolism. 2014 May;63(5):702-15. doi: 10.1016/j.metabol.2014.02.004. Epub 2014 Feb 11.
Cyclosporine 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 (5mg/kg/day) and SRL (1mg/kg/day) treatment for 3 and 9weeks on lipid metabolism, in Wistar rats.
MATERIALS/METHODS: Lipolysis 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.
CsA and SRL treatments of rats for 3 and 9weeks 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 9weeks, SRL treatment caused ectopic deposition of TG in the liver after 3weeks. Moreover, ACC1 and FAS protein expression was increased after 3weeks (>100%, p<0.01), while HSL was increased after 9weeks 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 3weeks of treatment.
The 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.
环孢素 A（CsA）和西罗莫司（SRL）是与移植后新发糖尿病和血脂异常相关的免疫抑制剂（IA）。我们旨在评估 CsA（5mg/kg/天）和 SRL（1mg/kg/天）治疗 3 周和 9 周对 Wistar 大鼠脂质代谢的分子影响。
材料/方法：在分离的脂肪细胞中评估脂肪分解，同时测量血清中的甘油三酯（TG）和非酯化脂肪酸（NEFA）。评估脂肪组织和肝脏中与脂质代谢相关的基因和蛋白表达。
CsA 和 SRL 治疗大鼠 3 周和 9 周分别使异丙肾上腺素刺激的脂肪分解增加 5-9 倍和 4-6 倍。虽然 CsA 增加了脂肪细胞的重量和直径，以及 9 周后循环中的 NEFA 和 TG 水平，但 SRL 治疗在 3 周后导致 TG 在肝脏中的异位沉积。此外，ACC1 和 FAS 蛋白表达在 3 周后增加（>100%，p<0.01），而 HSL 在 CsA 治疗 9 周后增加。另一方面，SRL 在 3 周治疗后降低了脂肪组织中脂肪生成基因的表达，包括 ACC1（50%，p<0.05）、lipin1（25%，p<0.05）、PPAR-γ（42%，p<0.05）和 SCD1（80%，p<0.001）。
两种 IA 对脂肪分解和脂肪生成基因表达的影响表明，这些药物影响脂质代谢，从而导致免疫抑制治疗期间观察到的血脂异常。
