2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13-15 September 2000, Toronto, Canada

INHIBITION OF ADIPOCYTE DIFFERENTIATION BY HIV-1 PROTEASE INHIBITORS: POTENTIAL MECHANISMS BASED ON CHANGES IN GENE EXPRESSION

Antiviral Therapy 2000; 5(Suppl. 5):26 (abstract no. P3)

GJ Stevens, AC Lankford, M Chen and B Jessen
Pfizer Global R&D, LaJolla Laboratories, San Diego, Calif., USA

BACKGROUND: Previous studies have shown that HIV protease inhibitors (PIs) decrease 3T3-L1 adipocyte differentiation, and preliminary data in our laboratory also demonstrated inhibition of human adipocyte differentiation by PIs. The mechanism for PI inhibition of adipocyte differentiation is unknown.

OBJECTIVES: The purpose of this study was to evaluate the changes in gene expression in PI-exposed pre-adipocytes undergoing adipocyte conversion.

DESIGN: Murine 3T3-L1 pre-adipocytes were converted into adipocytes in the presence of vehicle, nelfinavir or indinavir. Analysis of RNA was performed using Affymetrix murine GeneChip arrays. A similar study was also performed with human preadipocytes. PI concentrations ranged from 5 to 20 µM, depending on the sensitivity of the cell type.

RESULTS: Of the 11000 genes evaluated, PI treatment resulted in changes in expression of genes associated with cell cycle, mitochondrial function, metabolism, apoptosis, growth factors, signal transduction, cytoskeleton, extracellular matrix and transcription factors, as well as genes known to play an essential role in adipocyte differentiation. These included induction of calpain and GADD153 (both inhibit C/EBP signalling), as well as decreases in C/EBP delta. Since C/EBP is required for initial signalling and maintenance of the adipocyte phenotype, PIs may inhibit differentiation by preventing C/EBP activation. Since indinavir is a more potent inhibitor of 3T3-L1 adipocyte differentiation, changes specific to indinavir treatment were also identified. These changes included decreases in 11β-hydroxysteroid dehydrogenase-1 (11βHSD-1) and increases in glucocorticoid receptor, insulin-like growth factor, glycogen synthase-3, apolipoprotein C1, and ATP-binding transport protein.

CONCLUSIONS: The use of gene expression arrays may provide early clues to the potential mechanisms of HIV-associated body fat changes. These initial results demonstrate that PIs affect multiple pathways within adipocytes, including genes associated with lipid metabolism and adipocyte differentiation. Identifying HAART-affected pathways provides a first step in understanding their potential influence on HIV-associated body fat changes.

000913
P3

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