Effects of Rilpivirine on Human Adipocyte Differentiation, Gene Expression, and Release of Adipokines and Cytokines
Effects of Rilpivirine on Human Adipocyte Differentiation, Gene Expression, and Release of Adipokines and Cytokines
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DOI：
10.1128/aac.00104-12
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Villarroya, Francesc
中科院分区：
文献类型：
--
作者：
Diaz-Delfin, Julieta;Domingo, Pere;Villarroya, Francesc
利培韦林是一种非核苷类逆转录酶抑制剂(NNRTI)，最近被开发为HIV-1感染的初始抗逆转录病毒治疗的首选药物。作为抗逆转录病毒治疗的次要影响，脂类代谢紊乱，最终导致脂肪组织分布和功能紊乱是人们普遍关注的问题。Efavirenz是最常用的NNRTI，在患者中引起轻微的血脂紊乱效应，并在体外严重损害脂肪细胞的分化。在这项研究中，我们首次展示了利培韦林对人脂肪细胞分化、基因表达和调节蛋白(脂肪因子和细胞因子)释放的影响，并将它们与依法韦林引起的影响进行了比较。利培韦林抑制脂肪细胞分化，与脂肪生成主要调控因子过氧化体增殖物激活受体γ(PPAR Gamma)、CCAAT增强子结合蛋白α(C/EBPα)和类固醇调节元件结合转录因子1(SREBP-1)及其编码脂蛋白脂酶和脂肪因子瘦素和脂联素的靶基因表达受损有关。利培韦林也抑制脂肪细胞脂联素的释放，但仅在高浓度时，且不改变瘦素的释放。利培韦林仅在很高浓度(10mM)时才能诱导促炎细胞因子(IL-6和-8、单核细胞趋化蛋白-1[MCP-1]、纤溶酶原激活物抑制物-1[PAI-1])的释放。比较相同浓度(4 MU M)或低浓度(2 MU M)的利培韦林和依法韦仑对脂肪细胞的影响，发现利培韦林诱导的脂肪生成障碍和促炎细胞因子的表达和释放均明显低于依法韦连兹。结果表明，利培韦林仅在高浓度时引起抗脂肪和促炎反应模式，而依沙韦仑在低浓度时引起类似的效应。
Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation in vitro. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPAR gamma), CCAAT enhancer binding protein alpha (C/EBP alpha), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 [MCP-1], plasminogen activator inhibitor type 1 [PAI-1]) only at very high concentrations (10 mu M). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 mu M) or even at lower concentrations of efavirenz (2 mu M) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations.