Inhibition Of Human Preadipocyte Proteasomal Activity By Hiv Protease Inhibitors Or Specific Inhibitor Lactacystin Leads To A Defect In Adipogenesis, Which Involves Matrix Metalloproteinase-9

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)- kappa B 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-kappa B 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-kappa B inhibitor, I kappa B beta, 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-kappa B 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.