Rodríguez de la Concepción M Luisa, Yubero Pilar, Domingo Joan C, Iglesias Roser, Domingo Pere, Villarroya Frcancesc, Giralt Marta
Department de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
Antivir Ther. 2005;10(4):515-26.
Human adipose depots contain remnant brown adipocytes interspersed among white adipocytes, and disturbances of brown with respect to white adipocyte biology have been implicated in highly active antiretroviral therapy (HAART)-induced lipomatosis. Brown adipocytes express the uncoupling protein-1 (UCP1) and contain a large number of mitochondria, potential targets of HAART toxicity. The aim of this study was to evaluate the effects of reverse transcriptase inhibitors (RTIs) on primary brown adipocytes differentiated in culture.
We analysed the effects of RTIs, nucleoside analogues (NRTIs: stavudine, zidovudine, didanosine and lamivudine) and non-nucleoside analogues (NNRTIs: nevirapine and efavirenz), on differentiation, mitochondrial biogenesis and gene expression in brown adipocytes.
None of the NRTIs altered brown adipocyte differentiation whereas NNTRIs had differing effects. Efavirenz blocked lipid deposition and expression of adipose marker genes but nevirapine induced lipid accumulation and adipose gene expression, promoted mitochondrial biogenesis and increased UCP1. Stavudine, zidovudine and didanosine reduced mitochondrial DNA (mtDNA) content. However, mitochondrial genome expression was only impaired in didanosine-treated adipocytes. Stavudine, but not zidovudine, induced expression of the mitochondrial transcription factors and this may explain compensatory mechanisms for the depletion of mtDNA by up-regulating mtDNA transcription. Stavudine caused a specific induction of UCP1 gene expression through direct interaction with a retinoic acid-dependent pathway.
Specific disturbances in brown adipocytes in adipose depots may contribute to HAART-induced lipomatosis. Mitochondrial depletion does not appear to be the only mechanism explaining adverse effects in brown adipocytes because there is evidence of compensatory mechanisms that maintain mtDNA expression, and the expression of the UCP1 gene is specifically altered.
人体脂肪库中含有散布于白色脂肪细胞之间的残余褐色脂肪细胞，褐色脂肪细胞与白色脂肪细胞生物学特性的紊乱被认为与高效抗逆转录病毒疗法（HAART）引起的脂肪瘤形成有关。褐色脂肪细胞表达解偶联蛋白-1（UCP1）并含有大量线粒体，这是HAART毒性的潜在靶点。本研究的目的是评估逆转录酶抑制剂（RTIs）对培养中分化的原代褐色脂肪细胞的影响。
我们分析了RTIs、核苷类似物（NRTIs：司他夫定、齐多夫定、去羟肌苷和拉米夫定）和非核苷类似物（NNRTIs：奈韦拉平和依非韦伦）对褐色脂肪细胞分化、线粒体生物发生和基因表达的影响。
没有一种NRTIs改变褐色脂肪细胞的分化，而NNRTIs有不同的作用。依非韦伦阻断脂质沉积和脂肪标志物基因的表达，但奈韦拉平诱导脂质积累和脂肪基因表达，促进线粒体生物发生并增加UCP1。司他夫定、齐多夫定和去羟肌苷降低线粒体DNA（mtDNA）含量。然而，线粒体基因组表达仅在去羟肌苷处理的脂肪细胞中受损。司他夫定而非齐多夫定诱导线粒体转录因子的表达，这可能解释了通过上调mtDNA转录来补偿mtDNA耗竭的机制。司他夫定通过与视黄酸依赖性途径直接相互作用导致UCP1基因表达的特异性诱导。
脂肪库中褐色脂肪细胞的特定紊乱可能导致HAART诱导的脂肪瘤形成。线粒体耗竭似乎不是解释褐色脂肪细胞不良反应的唯一机制，因为有证据表明存在维持mtDNA表达的补偿机制，并且UCP1基因的表达发生了特异性改变。
