Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors
Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors
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DOI：
10.1074/jbc.m006474200
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发表时间：
2000-12-29
影响因子：
4.8
通讯作者：
Lanes, MD
中科院分区：
文献类型：
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作者：
Dowell, P;Flexner, C;Lanes, MD
许多人类免疫缺陷病毒(HIV)感染患者在接受包括HIV蛋白酶抑制剂在内的联合抗逆转录病毒治疗时，会经历周围皮下脂肪组织的萎缩。我们利用3T3-L1前脂肪细胞系研究了HIV蛋白水解酶抑制剂对脂肪细胞成脂和存活的影响。几种HIV蛋白酶抑制剂被发现要么抑制前脂肪细胞的分化，要么促进脂肪细胞的死亡。一种蛋白水解酶抑制剂奈非那韦强烈地引起这两种效应。在奈非那韦诱导分化时，3T3-L1前脂肪细胞不能积累细胞质中的三酰甘油，也不能表达正常水平的成脂转录因子CCAAT/增强子结合蛋白α和过氧化物酶体增殖物激活受体γ。在奈非那韦处理的细胞中，蛋白水解型、活性68 kDa形式的固醇调节元件结合蛋白-1的水平也显著降低，而这种蛋白的125 kDa前体形式的水平不受影响。奈非那韦的抑制作用发生在前体脂肪细胞分化、CCAAT/增强子结合蛋白β表达和有丝分裂克隆扩张期完成的关键早期事件之后，因为这些事件不受奈非那韦治疗的影响。此外，奈非那韦处理完全分化的3T3-L1脂肪细胞导致DNA链断裂和严重的细胞活力丧失。相比之下，奈非那韦对前脂肪细胞的细胞增殖和活性没有影响。因此，在获得脂肪细胞表型期间发生的分子或细胞变化增加了对奈非那韦诱导的细胞死亡的易感性。综合考虑，这些结果表明，奈非那韦可能通过影响脂肪细胞的活力和通过抑制前脂肪细胞的分化来阻止丢失的脂肪细胞的替换，从而促进脂肪组织的萎缩。
Many human immunodeficiency virus (HIV)-infected patients taking combination antiretroviral therapy that includes HIV protease inhibitors experience atrophy of peripheral subcutaneous adipose tissue. We investigated the effects of HIV protease inhibitors on adipogenesis and adipocyte survival using the 3T3-L1 preadipocyte cell line. Several HIV protease inhibitors were found either to inhibit preadipocyte differentiation or to promote adipocyte cell death. One protease inhibitor, nelfinavir, elicited both of these effects strongly. When induced to differentiate in the presence of nelfinavir, 3T3-L1 preadipocytes failed to accumulate cytoplasmic triacylglycerol and failed to express normal levels of the adipogenic transcription factors CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. The level of the proteolytically processed, active 68-kDa form of sterol regulatory element-binding protein-1, a transcription factor known to promote lipogenic gene expression, also was reduced markedly in nelfinavir-treated cells, whereas the level of the 125-kDa precursor form of this protein was unaffected. The inhibitory effect of nelfinavir occurred subsequent to critical early events in preadipocyte differentiation, expression of CCAAT/enhancer-binding protein beta and completion of the mitotic clonal expansion phase, because these events were unaffected by nelfinavir treatment. In addition, nelfinavir treatment of fully differentiated 3T3-L1 adipocytes resulted in DNA strand cleavage and severe loss of cell viability. In contrast, cell proliferation and viability of preadipocytes were unaffected by nelfinavir treatment. Thus, molecular or cellular changes that occur during acquisition of the adipocyte phenotype promote susceptibility to nelfinavir-induced cell death. When considered together, these results suggest that nelfinavir may promote adipose tissue atrophy by compromising adipocyte viability and preventing replacement of lost adipocytes by inhibiting preadipocyte differentiation.