Very low density lipoprotein receptor promotes adipocyte differentiation and mediates the proadipogenic effect of peroxisome proliferator-activated receptor gamma agonists.
Very low density lipoprotein receptor promotes adipocyte differentiation and mediates the proadipogenic effect of peroxisome proliferator-activated receptor gamma agonists.
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DOI：
10.1016/j.bcp.2011.09.003
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发表时间：
2011-12
影响因子：
5.8
通讯作者：
H. Tao;T. Hajri
中科院分区：
文献类型：
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作者：
H. Tao;T. Hajri
极低密度脂蛋白受体（VLDLR）是低密度受体家族的成员，主要在脂肪组织、心脏和骨骼肌中表达。VLDLR结合富含载脂蛋白-E-磷脂酰肌醇的脂蛋白，并在脂质代谢中起关键作用。在脂肪细胞中，VLDLR表达随着分化而增加，但不知道它是否在脂肪形成中起作用。在这里，我们报告了3 T3-L1脂肪细胞中的VLDLR表达被PPARγ激动剂15-脱氧-delta 12，14-前列腺素J2（15 d-PGJ 2）以剂量和时间依赖性方式上调。用siRNA敲低过氧化物酶体增殖物激活受体-γ（PPARγ）可消除吡格列酮和15 d-PGJ 2诱导的VLDLR表达，同时减少脂肪细胞中的VLDL摄取。此外，对照小鼠脂肪细胞（vldlr+/+）的PPARγ激动剂处理增强了脂肪生成和VLDL摄取，同时诱导了VLDLR表达。然而，vldlr缺乏（vldlr−/−）显著减弱了PPARγ激动剂的促脂肪形成作用。序列分析显示vldlr启动子内存在一个推定的PPARγ应答序列（PPRE），该序列对天然（15 d-PGJ 2）和合成（吡格列酮）PPARγ激动剂有应答。使用5′-侧翼区的连续缺失的报告基因分析表明，该推定的PPRE位点诱导启动子反式激活，而位点靶向突变废除反式激活。电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）分析显示，PPAR-Y与PPRE序列特异性结合。总之，这些结果支持VLDLR在脂肪细胞分化和介导PPARγ的促脂肪形成作用中的关键功能。
Very low density lipoprotein receptor (VLDLR) is a member of the low density receptor family, expressed mostly in adipose tissue, heart, and skeletal muscles. VLDLR binds apolipoprotein-E-triglyceride-rich lipoproteins and plays a key role in lipid metabolism. In adipocytes, VLDLR expression increases with differentiation but it is not known whether it plays a role in the adipogenesis. Here we report that VLDLR expression in 3T3-L1 adipocytes is upregulated by PPARγ agonist 15-deoxy-delta12,14-prostaglandin J2(15d-PGJ2) in dose- and time-dependant manners. Knockdown of peroxisome proliferator-activated receptor-γ (PPARγ) with siRNA abolished pioglitazone- and 15d-PGJ2-induced VLDLR expression and simultaneously reduced VLDL uptake in adipocytes. In addition, PPARγ-agonist treatment of control mouse adipocytes (vldlr+/+) enhanced adipogenesis and VLDL uptake concurrently with the induction of VLDLR expression. However, vldlr deficiency (vldlr−/−) significantly blunted the proadipogenic effects of PPARγ agonists. Sequence analysis revealed the presence of a putative PPARγ responsive sequence (PPRE) within the vldlr promoter, which is responsive to natural (15d-PGJ2) and synthetic (pioglitazone) PPARγ agonists. Reporter gene assays using serial deletion of the 5′-flanking region showed that this putative PPRE site induced promoter transactivation, while a site-targeted mutation abolished transactivation. Moreover, electrophoresis mobility shift assay (EMSA) and chromatic immunoprecipitation (ChIP) assays showed the specific binding of PPARγ to the PPRE sequence. Together, these results support a crucial function for VLDLR in adipocyte differentiation and mediation of the proadipogenic effect of PPARγ.