The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
Mol Cell Endocrinol. 2013 Jan 30;365(2):260-9. doi: 10.1016/j.mce.2012.10.030. Epub 2012 Nov 15.
Cyclosporin A (CsA), tacrolimus and rapamycin are immunosuppressive agents (IAs) associated with insulin resistance and dyslipidemia, although their molecular effects on lipid metabolism in adipose tissue are unknown. We explored IAs effects on lipolysis, lipid storage and expression of genes involved on lipid metabolism in isolated human adipocytes and/or adipose tissue obtained via subcutaneous and omental fat biopsies. CsA, tacrolimus and rapamycin increased isoproterenol-stimulated lipolysis and inhibited lipid storage by 20-35% and enhanced isoproterenol-stimulated hormone-sensitive lipase Ser552 phosphorylation. Rapamycin also increased basal lipolysis (~20%) and impaired insulin's antilipolytic effect. Rapamycin, down-regulated the gene expression of perilipin, sterol regulatory element-binding protein 1 (SREBP1) and lipin 1, while tacrolimus down-regulated CD36 and aP2 gene expression. All three IAs increased IL-6 gene expression and secretion, but not expression and secretion of TNF-α or adiponectin. These findings suggest that CsA, tacrolimus and rapamycin enhance lipolysis, inhibit lipid storage and expression of lipogenic genes in adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
环孢素 A（CsA）、他克莫司和雷帕霉素是与胰岛素抵抗和血脂异常相关的免疫抑制剂（IA），尽管它们对脂肪组织中脂质代谢的分子影响尚不清楚。我们探讨了 IA 对离体人脂肪细胞和/或通过皮下和网膜脂肪活检获得的脂肪组织中的脂肪分解、脂质储存以及参与脂质代谢的基因表达的影响。CsA、他克莫司和雷帕霉素增加异丙肾上腺素刺激的脂肪分解，并抑制脂质储存 20-35%，增强异丙肾上腺素刺激的激素敏感脂肪酶 Ser552 磷酸化。雷帕霉素还增加基础脂肪分解（~20%）并损害胰岛素的抗脂肪分解作用。雷帕霉素下调了脂肪细胞中 perilipin、固醇调节元件结合蛋白 1（SREBP1）和 lipin 1 的基因表达，而他克莫司下调了 CD36 和 aP2 基因的表达。这三种 IA 均增加了 IL-6 基因的表达和分泌，但不增加 TNF-α或脂联素的表达和分泌。这些发现表明，CsA、他克莫司和雷帕霉素增强脂肪组织中的脂肪分解、抑制脂质储存和生脂基因的表达，这可能导致与免疫抑制治疗相关的血脂异常和胰岛素抵抗的发展。
