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.
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.
Mondal
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D
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Larussa
V F
VF
Agrawal
K C
KC
D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D019469:Indinavir / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D017320:HIV Protease Inhibitors; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D012097:Repressor Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019469:Indinavir; D005947:Glucose; D019438:Ritonavir