Synergistic antiadipogenic effects of HIV type 1 protease inhibitors with tumor necrosis factor alpha: suppression of extracellular insulin action mediated by extracellular matrix-degrading proteases.

Abstract

Long-term use of HIV-1 protease inhibitors (PIs) is associated with a lipodystrophy syndrome. To delineate the associated mechanisms, adipogenesis was determined in 3T3-L1 cells in the presence or absence of either indinavir (2-50 microg/ml) or ritonavir (0.4-10 microg/ml). A concentration-dependent decrease in both lipid (4-59%) and triglyceride (11-49%) levels was seen after 10 days of exposure. Simultaneous treatment with TNF-alpha showed a synergistic suppression in lipid levels by 45-95% at 10 U/ml and almost complete suppression at 100 U/ml. The effect of PIs on insulin-induced lipogenesis was monitored by [(14)C)]glucose incorporation into lipids, which was suppressed by 21-86% in a concentration-dependent manner. Insulin-sensitizing agent, troglitazone (80 and 400 nM), effectively blocked the PI-mediated adipogenic suppression. Preadipocyte factor 1 gene (pref-1) expression, as monitored by RT-PCR, was downregulated (4- to 6-fold) within 48 hr after insulin stimulation; however, a smaller decrease (1.2- to 1.8-fold) was observed in PI-exposed cells. The decrease in proteolytic activity of matrix metalloproteases (MMP-2 and MMP-9) during adipogenesis was reversed on exposure to the PIs. Similarly, the plasminolytic activity was increased and plasminogen activator inhibitor (PAI) activity was decreased in supernatants from PI-treated cells. The insulin-mediated induction (3- to 4-fold) of PAI-1 and PAI-2 message was suppressed on exposure to PIs, which was reversed by troglitazone treatment. Thus, the HIV-1 PIs may suppress adipogenesis by disrupting the concerted actions of host proteases that regulate ECM integrity required for initiation of differentiation.

• Authors: D Mondal, V F Larussa, K C Agrawal
• Journal: AIDS research and human retroviruses (AIDS Res Hum Retroviruses) Vol. 17 Issue 17 Pg. 1569-84 (Nov 20 2001) ISSN: 0889-2229 [Print] United States
• PMID: 11779345 (Publication Type: Journal Article)

Chemical References

• Calcium-Binding Proteins
• Dlk1 protein, mouse
• HIV Protease Inhibitors
• Insulin
• Intercellular Signaling Peptides and Proteins
• Membrane Proteins
• Plasminogen Activator Inhibitor 1
• Plasminogen Activator Inhibitor 2
• Repressor Proteins
• Triglycerides
• Tumor Necrosis Factor-alpha
• Indinavir
• Glucose
• Ritonavir

Topics

• Adipocytes (cytology, drug effects)
• Animals
• Calcium-Binding Proteins
• Cell Differentiation (drug effects)
• Cells, Cultured
• Drug Synergism
• Glucose (metabolism)
• HIV Protease Inhibitors (pharmacology)
• Indinavir (pharmacology)
• Insulin (metabolism)
• Intercellular Signaling Peptides and Proteins
• Lipid Metabolism
• Membrane Proteins (drug effects, genetics, metabolism)
• Mice
• Plasminogen Activator Inhibitor 1 (metabolism)
• Plasminogen Activator Inhibitor 2 (metabolism)
• Repressor Proteins (drug effects, genetics, metabolism)
• Ritonavir (pharmacology)
• Triglycerides (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)