Human immunodeficiency virus protease inhibitors accumulate into cultured human adipocytes and alter expression of adipocytokines
Authors: Gérard Ailhaud
Hubert Vidal
Françoise Cottrez
Daniele Duval
Cécile Vernochet
Stéphane Azoulay
Christian Dani
Roger Guedj
Journal: Journal of Biological Chemistry (2005)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Lipodystrophic syndrome; highly active antiviral therapy; adipocyte gene expression; adipocytokines; HIV drugs
Affiliations: Institut Signalisation, Biologie du Développement et Cancer, UMR 6543 CNRS, Centre de Biochimie, 06108 Nice, France.

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. 

Retracted: No

PubPeer comments:
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 In the Corrigendum, the authors replaced Figures 2 and 7B without changing the main text. In the new Fgiure 2B, the original main text  Exposure of cells to 100 nM PMA resulted in a time-dependent induction of HIF-1u03b1 that peaked at 4u20136 h and decreased gradually but did not return to the basal level (Fig. 2B) should be changed to  Exposure of cells to 100 nM PMA resulted in a time-dependent induction of HIF-1u03b1 that peaked at 2u20134 h and decreased gradually to the basal level (Fig. 2B) In the new Figure 7B, the original main text  The phosphorylation peaked at 48 h and remained elevated at 72 h (Fig. 7B). The total protein levels of ERK and AKT were constant during the process (Fig. 7, A and B). is completely wrong, since the total protein levels of AKT increased by time like p-Akt. This indicates that the Akt phosphorylation was not affected by PMA after 24 h stimulation. It looks like the corrections affect the conclusions of the figures. However, they described that  The authors assert that the corrections do not affect the conclusions of the figures or the study. ,