title: Human immunodeficiency virus protease inhibitors accumulate into cultured human adipocytes and alter expression of adipocytokines.
abstract: Lipodystrophic syndrome is a major side effect of highly active antiviral therapy. Fat tissue redistribution is associated with changes in adipocyte gene expression and in circulating levels of adipocytokines involved in the development of insulin resistance. However, the evidence that HIV drugs accumulate into human adipocytes and have a direct effect on the expression of adipocyte-specific genes is still lacking. To address these questions, we used adipocytes derived from adult stem (hMADS) cells isolated from human adipose tissue. We showed by ELISA that two inhibitors of the HIV protease, lopinavir and ritonavir, accumulated at similar levels during the development of hMADS cells in adipocytes, whereas a non-nucleoside reverse transcriptase inhibitor, the nevirapine, accumulated at lower levels. Two fluorescent protease inhibitors then have been generated to investigate their subcellular localization. The data showed that HIV drugs accumulated into adipocytes and displayed various effects on hMADS cell-derived adipocytes. Indinavir, amprenavir, and nevirapine did not alter differentiation of precursor cells. In contrast, lopinavir, saquinavir, and ritonavir inhibited the development of preadipocytes into adipocytes. In adipocytes, amprenavir increased leptin expression and ritonavir was able to up-regulate tumor necrosis factor-alpha, interleukin 6, and leptin expression and down-regulate the expression of peroxisome proliferator-activated receptor gamma and adiponectin. Intracellular accumulation and localization of HIV drugs into human adipocytes strongly suggest that adipose tissues store these drugs. Because ritonavir can alter the expression of insulin resistance-related cytokines in human adipocytes in a way parallel to the situation observed in vivo upon treatment of HIV-infected patients, we propose that protease inhibitors participate in insulin resistance through a direct effect on adipocytes.
authors.affiliation: Institut Signalisation, Biologie du Développement et Cancer, UMR 6543 CNRS, Centre de Biochimie, 06108 Nice, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vernochet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Azoulay
authors.forename: Daniele
authors.initials: D
authors.lastname: Duval
authors.forename: Roger
authors.initials: R
authors.lastname: Guedj
authors.forename: Françoise
authors.initials: F
authors.lastname: Cottrez
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.forename: Gérard
authors.initials: G
authors.lastname: Ailhaud
authors.forename: Christian
authors.initials: C
authors.lastname: Dani
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007333:Insulin Resistance; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet
chemical_list: D016207:Cytokines; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors