Wu J, Zhu Y H, Patel S B
Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston, South Carolina 29425-2222, USA.
Am J Physiol. 1999 Dec;277(6):E1087-94. doi: 10.1152/ajpendo.1999.277.6.E1087.
The use of cyclosporin A has contributed greatly to the success of organ transplantation. However, cyclosporin-associated side effects of hypertension, nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the accelerated atherosclerosis observed posttransplantation. Using a mouse model, we treated Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of cyclosporin and observed significant elevations of plasma cholesterol, triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone treated control animals. Measurement of the rate of secretion of very low-density lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to a significant increase in the rate of hepatic VLDL triglyceride secretion. Total apoB secretion was unaffected. Northern analysis showed that cyclosporin A treatment increased the abundance of hepatic mRNA levels for a number of key genes involved in cholesterol biosynthesis relative to vehicle-alone treated animals. Two key transcriptional factors, sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2 expression was increased at the mRNA level, and there was an increase in the active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were reduced. These results show that the molecular mechanisms by which cyclosporin causes dyslipoproteinemia may, in part, be mediated by selective activation of SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic secretion of VLDL triglyceride.
环孢素A的使用对器官移植的成功起到了极大的推动作用。然而，环孢素相关的高血压、肾毒性和血脂异常等副作用削弱了这些益处。环孢素诱导的血脂异常可能是移植后观察到的动脉粥样硬化加速的一个重要危险因素。我们使用小鼠模型，以每日20微克/克体重的剂量给瑞士韦伯斯特小鼠连续治疗6天，相对于仅用赋形剂处理的对照动物，观察到血浆胆固醇、甘油三酯和载脂蛋白B（apoB）水平显著升高。对肝脏在体内极低密度脂蛋白（VLDL）分泌速率的测量表明，环孢素治疗导致肝脏VLDL甘油三酯分泌速率显著增加。总apoB分泌未受影响。Northern分析显示，相对于仅用赋形剂处理的动物，环孢素A治疗增加了肝脏中一些参与胆固醇生物合成的关键基因的mRNA水平丰度。两种关键转录因子，即固醇调节元件结合蛋白（SREBP）-1和SREBP-2，也表现出差异表达；SREBP-2的mRNA水平升高，活性核形式增加，而SREBP-1的mRNA和核形式减少。这些结果表明，环孢素导致血脂异常的分子机制可能部分是由SREBP-2的选择性激活介导的，从而导致脂质代谢基因表达增强和肝脏VLDL甘油三酯分泌增加。
