title: Effects of rilpivirine on human adipocyte differentiation, gene expression, and release of adipokines and cytokines.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institut de Biomedicina, IBUB, University of Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
authors.forename: Julieta
authors.initials: J
authors.lastname: Díaz-Delfín
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: Maria Gracia
authors.initials: MG
authors.lastname: Mateo
authors.forename: Maria Del Mar
authors.initials: Mdel M
authors.lastname: Gutierrez
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Domingo
authors.forename: Marta
authors.initials: M
authors.lastname: Giralt
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D054392:Adipokines; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes; D016207:Cytokines; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009570:Nitriles / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D000068696:Rilpivirine; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D054392:Adipokines; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D022763:CCAAT-Enhancer-Binding Protein-alpha; D003521:Cyclopropanes; D016207:Cytokines; D009570:Nitriles; D047495:PPAR gamma; D011743:Pyrimidines; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D000068696:Rilpivirine; C098320:efavirenz