De Barros Sandra, Zakaroff-Girard Alexia, Lafontan Max, Galitzky Jean, Bourlier Virginie
Unité de Recherche sur les Obésites, Institut National de la Santé et de la Recherche Médical Unité 586, Institut Louis Bugnard, Hopital Rangueil, Université Paul Sabatier, Toulouse, France.
J Pharmacol Exp Ther. 2007 Jan;320(1):291-9. doi: 10.1124/jpet.106.111849. Epub 2006 Oct 12.
In a previous publication, we reported that human immunodeficiency virus (HIV) protease inhibitors (PIs) inhibited the differentiation of human preadipocytes in primary culture, reducing the expression and secretion of matrix metalloproteinase 9 (MMP-9). The present work was performed to clarify this mechanism. Interestingly, HIV-PIs have been reported to be inhibitors of the proteasome complex, which is known to regulate nuclear factor (NF)-kappaB activation and transcription of its target genes, among them MMP-9. We thus investigated the potential involvement of the proteasome in the antiadipogenic effects of HIV-PIs. The effect of four HIV-PIs was tested on preadipocyte proteasomal activity, and chronic treatment with the specific proteasome inhibitor lactacystin was performed to evaluate alterations of adipogenesis and MMP-9 expression/secretion. Finally, modifications of the NF-kappaB pathway induced by either HIV-PIs or lactacystin were studied. We demonstrated that preadipocyte proteasomal activity was decreased by several HIV-PIs and that chronic treatment with lactacystin mimicked the effects of HIV-PIs by reducing adipogenesis and MMP-9 expression/secretion. Furthermore, we observed an intracellular accumulation of the NF-kappaB inhibitor, IkappaBbeta, with chronic treatment with HIV-PIs or lactacystin as well as a decrease in MMP-9 expression induced by acute tumor necrosis factor-alpha stimulation. These results indicate that inhibition of the proteasome by specific (lactacystin) or nonspecific (HIV-PIs) inhibitors leads to a reduction of human adipogenesis, and they therefore implicate deregulation of the NF-kappaB pathway and the related decrease of the key adipogenic factor, MMP-9. This study adds significantly to recent reports that have linked HIV-PI-related lipodystrophic syndrome with altered proteasome function, endoplasmic reticulum stress, and metabolic disorders.
在之前的一篇出版物中，我们报道了人类免疫缺陷病毒（HIV）蛋白酶抑制剂（PIs）抑制原代培养的人前脂肪细胞分化，降低基质金属蛋白酶9（MMP-9）的表达和分泌。开展本研究以阐明该机制。有趣的是，据报道HIV-PIs是蛋白酶体复合物的抑制剂，已知该复合物可调节核因子（NF）-κB的激活及其靶基因的转录，其中包括MMP-9。因此，我们研究了蛋白酶体在HIV-PIs抗脂肪生成作用中的潜在参与情况。测试了四种HIV-PIs对前脂肪细胞蛋白酶体活性的影响，并使用特异性蛋白酶体抑制剂乳胞素进行慢性处理，以评估脂肪生成及MMP-9表达/分泌的改变。最后，研究了HIV-PIs或乳胞素诱导的NF-κB信号通路的变化。我们证明几种HIV-PIs可降低前脂肪细胞蛋白酶体活性，并且用乳胞素进行慢性处理通过减少脂肪生成及MMP-9表达/分泌模拟了HIV-PIs的作用。此外，我们观察到，用HIV-PIs或乳胞素进行慢性处理后，NF-κB抑制剂IkappaBbeta在细胞内积累，并且急性肿瘤坏死因子-α刺激诱导的MMP-9表达降低。这些结果表明，特异性（乳胞素）或非特异性（HIV-PIs）抑制剂对蛋白酶体的抑制导致人类脂肪生成减少，因此提示NF-κB信号通路失调以及关键脂肪生成因子MMP-9相关的减少。这项研究显著补充了最近将HIV-PI相关脂肪代谢障碍综合征与蛋白酶体功能改变、内质网应激和代谢紊乱联系起来的报道。
