Abstract
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)-κB 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-κB 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-κB inhibitor, IκBβ, with chronic treatment with HIV-PIs or lactacystin as well as a decrease in MMP-9 expression induced by acute tumor necrosis factor-α 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-κB 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.
Footnotes
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This work was supported by Grants 01 128 and 02 197 from the Agence Nationale de Recherche sur le SIDA et les hépatites virales.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.111849.
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ABBREVIATIONS: IκB, inhibitor of nuclear factor-κB; NF-κB, nuclear factor-κB; HIV, human immunodeficiency virus; PI, protease inhibitor; AT, adipose tissue; MMP, matrix metalloproteinase; SQV, saquinavir; NFV, nelfinavir; TNF, tumor necrosis factor; Bay 11-7802, (E)-3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile; IDV, indinavir; RTV, ritonavir; RFU, relative fluorescence units; TBST, Tris-buffered saline/Tween 20; RT, reverse transcriptase; PCR, polymerase chain reaction; aP2, fatty acid binding protein; HSL, hormone-sensitive lipase; ANOVA, analysis of variance. MG-132, carbobenzoxy-l-leucyl-l-leucyl-l-leucinal; TG, triglyceride.
- Received August 2, 2006.
- Accepted October 10, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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