1. Human Immunodeficiency Virus Protease Inhibitors Accumulate into Cultured Human Adipocytes and Alter Expression of Adipocytokines
- Author
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Cécile Vernochet, Stéphane Azoulay, Christian Dani, Roger Guedj, Hubert Vidal, Gérard Ailhaud, Daniele Duval, Françoise Cottrez, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratoire de Chimie des Molécules Bioactives et des Arômes (LCMBA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Interactions cellulaires en immunologie et immunopathologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanisme Moléculaire du Diabète (MMD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Oillaux, Genevieve
- Subjects
Adipocytes ,Cell Differentiation ,Chromatography ,High Pressure Liquid ,Cytokines ,Enzyme-Linked Immunosorbent Assay ,HIV Protease Inhibitors ,Humans ,Insulin Resistance ,Reverse Transcriptase Inhibitors ,Spectrophotometry ,Ultraviolet ,Adipose tissue ,Biochemistry ,chemistry.chemical_compound ,MESH: Spectrophotometry, Ultraviolet ,Adipocyte ,HIV Protease Inhibitor ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Chromatography, High Pressure Liquid ,MESH: Cytokines ,0303 health sciences ,Biologie du développement ,MESH: Enzyme-Linked Immunosorbent Assay ,virus diseases ,Lopinavir ,Development Biology ,3. Good health ,MESH: Insulin Resistance ,Adipogenesis ,medicine.drug ,MESH: Cell Differentiation ,medicine.medical_specialty ,Biology ,03 medical and health sciences ,Amprenavir ,Internal medicine ,[SDV.BDD] Life Sciences [q-bio]/Development Biology ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,SDV:BBM ,medicine ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Chromatography, High Pressure Liquid ,Molecular Biology ,MESH: Adipocytes ,MESH: HIV Protease Inhibitors ,030304 developmental biology ,MESH: Humans ,030306 microbiology ,Cell Biology ,Endocrinology ,chemistry ,Spectrophotometry, Ultraviolet ,Ritonavir ,MESH: Reverse Transcriptase Inhibitors ,Saquinavir - Abstract
International audience; 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.
- Published
- 2005
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