The therapeutic role of very low-density lipoprotein receptor gene in hyperlipidemia in type 2 diabetic rats.
The therapeutic role of very low-density lipoprotein receptor gene in hyperlipidemia in type 2 diabetic rats.
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DOI：
10.1089/hum.2010.038
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发表时间：
2011-02
影响因子：
4.2
通讯作者：
G. Yuan;Yongjian Liu;Tingting Sun;Yongping Xu;Jian-hua Zhang;Yan Yang;Mu-xun Zhang;K. Cianflone;Daowen Wang
中科院分区：
文献类型：
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作者：
G. Yuan;Yongjian Liu;Tingting Sun;Yongping Xu;Jian-hua Zhang;Yan Yang;Mu-xun Zhang;K. Cianflone;Daowen Wang
高血压是2型糖尿病的常见特征，与心血管疾病有关。极低密度脂蛋白受体（VLDLR）以高特异性结合并内化富含磷脂酰肌醇的脂蛋白。在这项研究中，我们评估了VLDLR在2型糖尿病大鼠高脂血症中的作用。通过注射低剂量链脲佐菌素结合高脂饮食在雄性Wistar大鼠中诱导2型糖尿病。将编码人VLDLR基因的重组腺相关病毒（rAAV·VLDLR）经静脉注射给糖尿病大鼠。结果显示，与正常大鼠相比，高胆固醇血症、高甘油三酯血症糖尿病大鼠骨骼肌（I型VLDLR主要减少）和脂肪组织（II型VLDLR主要减少）中VLDLR mRNA和蛋白水平均显著降低，但心脏中VLDLR mRNA和蛋白水平无明显变化。在体外培养的3 T3-L1脂肪细胞中，胰岛素诱导的胰岛素抵抗（1.0 mmol/L）显著降低了VLDLR mRNA的表达。在大鼠中，rAAV·VLDLR递送导致血清胆固醇和甘油三酯降低，持续研究期间（12周）。与未治疗的糖尿病大鼠相比，rAAV·VLDLR组的空腹血胰岛素显著较低，尽管在研究结束时两组的空腹血糖水平没有显著差异。rAAV·VLDLR处理的动物具有显著增加的脂蛋白脂酶活性和减少的主动脉粥样硬化。综上所述，我们的数据表明，2型糖尿病和相关的胰岛素抵抗表现为VLDLR降低，血清胆固醇和甘油三酯水平升高，通过单次注射rAAV·VLDLR过表达VLDLR逆转了这些作用，从而减轻了主动脉粥样硬化斑块的进展。
Hyperlipidemia is a common feature of type 2 diabetes and is related to cardiovascular disease. The very low-density lipoprotein receptor (VLDLR) binds to and internalizes triglyceride-rich lipoproteins with high specificity. In this study, we evaluated the role of VLDLR in hyperlipidemia in type 2 diabetic rats. Type 2 diabetes was induced in male Wistar rats by injection of low-dose streptozotocin coupled with a high-fat diet. Recombinant adeno-associated viral (rAAV) vectors encoding the human VLDLR gene (rAAV·VLDLR) were intravenously administered to diabetic rats. Results showed that in vivo, total VLDLR mRNA and protein levels were significantly decreased in skeletal muscle (type I VLDLR mainly reduced) and adipose tissue (type II VLDLR mainly reduced) but not in heart in hypercholesterolemic, hypertriglyceridemic diabetic rats compared with normal rats. And in vitro, in 3T3-L1 adipocytes, insulin-induced (1.0 mmol/liter) insulin resistance significantly decreased VLDLR mRNA expression. In rats, rAAV·VLDLR delivery resulted in a reduction in serum cholesterol and triglyceride that lasted for the duration of the study (12 weeks). Fasting blood insulin was significantly lower in the rAAV·VLDLR group versus untreated diabetic rats although fasting blood glucose levels were not significantly different in both groups at the end of the study. rAAV·VLDLR-treated animals had significantly increased lipoprotein lipase activity and reduced aortic atherosclerosis. Taken together, our data suggest that type 2 diabetes and related insulin resistance manifest decreased VLDLR with elevated serum cholesterol and triglyceride levels, and overexpression of VLDLR through a single injection of rAAV·VLDLR reversed these effects and consequentially attenuated aorta atherosclerotic plaque progression.