5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 8–11 July 2003, Le Meridien Montparnasse, Paris, France

EFFECTS OF HIV PROTEASE INHIBITORS IN HUMAN ADIPOSE TISSUE DIFFERENTIATION – INVOLVEMENT OF MATRIX METALLOPROTEINASES

Antiviral Therapy 2003; 8:L23 (abstract 25)

V Bourlier¹, A Zakaroff-Girard¹, C Pizzacalla¹, V Durand de Saint Front¹, J Galitzky¹, M Lafontan¹ and A Bouloumié-Diehl^2
1U586, Toulouse, France; and ²Institut for Cardiovascular Physiology, Frankfurt am Main, Germany

BACKGROUND: Lipodystrophy is a major side effect of antiretroviral therapy, but its pathophysiology remains elusive. Several studies have reported a decrease in murine adipocyte differentiation under HIV protease inhibitors (PIs) treatment but few data are available concerning the effects of PIs on human adipocytes. We have recently shown that matrix metalloproteinases (MMPs)-2 and -9, secreted by murine and human adipocytes, are involved in the modulation of adipocyte differenciation since their inhibition by the specific inhibitor batimastat led to significant reduction in murine adipocyte differentiation.

OBJECTIVES/AIM: We compared the effects of PIs and batimastat on the differentiation of primary cultures of human preadipocytes and studied the potential interaction between PIs and MMPs.

METHODS: Stromal human preadipocytes were isolated from human subcutaneous adipose tissue. After a 3-day priming period with ciglitazone (TZD), PIs (5, 10, 25 and 50 µM) or batimastat (1, 5 and 10 µM) were added to the TZD-free adipogenic medium for 10 days. The adipocyte differentiation was studied by the measurement of lipogenic (triglycerides) and lipolytic (hormone-sensitive lipase, HSL) markers. Expression and secretion of MMPs were determined by real-time RT-PCR analysis and gelatin zymography, respectively. The potency of the inhibitors on the activity of human recombinant MMPs was determined using a specific fluorescent substrate.

RESULTS: Indinavir and, to a better extent, saquinavir led to a reduction of the intracellular triglyceride content and were associated with a decrease in the expression of HSL. A similar effect was observed when the cells were treated with batimastat. Both PIs significantly reduced the secretion and the expression of MMP-9, without affecting the secretion of MMP-2. Moreover, no direct effect of PIs on the activity of recombinant MMPs was evidenced.

CONCLUSION/DISCUSSION: HIV PIs treatment led to the reduction of human adipocyte differentiation as was observed with the MMP inhibitor batimastat treatment. Although PIs did not affect directly the activity of MMPs, our results suggest that the inhibitory effect of PIs on human adipocyte differentiation might be mediated through the specific reduction of the adipocyte-derived expression and secretion of MMP-9.

Presenting author: V Bourlier

2003-07-08
25

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