Effects of Rilpivirine on Human Adipocyte Differentiation, Gene Expression, and Release of Adipokines and Cytokines

• Published in: Antimicrobial Agents and Chemotherapy 2012-06, Vol.56 (6), p.3369-3375
• Main Authors: Díaz-Delfín, Julieta, Domingo, Pere, Mateo, Maria Gracia, Gutierrez, Maria del Mar, Domingo, Joan Carles, Giralt, Marta, Villarroya, Francesc
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; adipogenesis; Adipokines; Adiponectin; Adipose tissue; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Benzoxazines - pharmacology; binding proteins; Biological and medical sciences; CCAAT-Enhancer-Binding Protein-alpha - metabolism; CCAAT/enhancer-binding protein; Cell Differentiation - drug effects; Cells, Cultured; chemokines; Cytokines; Differentiation; Drugs; Efavirenz; Gene expression; Gene Expression - drug effects; genes; HIV infections; Human immunodeficiency virus 1; Humans; Infection; Inflammation; Interleukin 6; Leptin; Lipid metabolism; Lipoprotein lipase; Medical sciences; Monocyte chemoattractant protein 1; Nitriles; Nitriles - pharmacology; non-nucleoside reverse transcriptase inhibitors; patients; Peroxisome proliferator-activated receptors; Pharmacology. Drug treatments; plasminogen activator; Plasminogen activator inhibitors; PPAR gamma - metabolism; Pyrimidines; Pyrimidines - pharmacology; regulatory proteins; Regulatory sequences; Rilpivirine; RNA-directed DNA polymerase; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterols; tissue distribution; Transcription factors
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00104-12

Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation in vitro. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer binding protein alpha (C/EBPα), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 [MCP-1], plasminogen activator inhibitor type 1 [PAI-1]) only at very high concentrations (10 μM). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 μM) or even at lower concentrations of efavirenz (2 μM) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations.