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)-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.
De Barros
Sandra
S
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.
Zakaroff-Girard
Alexia
A
Lafontan
Max
M
Galitzky
Jean
J
Bourlier
Virginie
V
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017667:Adipocytes / Q000201:enzymology*; D050156:Adipogenesis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D009570:Nitriles / Q000494:pharmacology; D061988:Proteasome Inhibitors; D013234:Stem Cells / Q000201:enzymology*; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D017320:HIV Protease Inhibitors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D009570:Nitriles; D061988:Proteasome Inhibitors; D013450:Sulfones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C067713:lactacystin; D000072000:NF-KappaB Inhibitor alpha; D020780:Matrix Metalloproteinase 9; D000111:Acetylcysteine