Effects of antiretroviral drug combinations on the differentiation of adipocytes.
OBJECTIVE
Preadipocyte cell lines present a cell model with which to understand the physiopathological mechanisms underlying lipodystrophy syndrome, a common complication observed in patients treated with highly active antiretroviral therapy (HAART) that, in general, is associated with the use of protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI). The aim of this study was to evaluate the effects of NRTI and of PI and NRTI combinations in this cell model.


METHODS
The differentiation of 3T3-F442A cells was studied by monitoring the expression of specific genes in the presence of therapeutic concentrations of antiretroviral drugs. Messenger RNA (mRNA) was quantified by two reverse transcription-PCR-based methods.


RESULTS
In the presence of 2 microM saquinavir, 30 microM ritonavir or 1 microM zidovudine preadipocytes delayed their differentiation, whereas the use of 10 microM nelfinavir led to cell death. Indinavir (10 microM) promoted lipoprotein lipase expression whereas 1 microM lamivudine or 1 microM stavudine enhanced slightly the expression of the malic enzyme gene. However, the combination of indinavir, lamivudine and stavudine led to a large increase in both lipoprotein lipase and malic enzyme mRNA transcription whereas the combination of indinavir, lamivudine and zidovudine led to a 2.5-fold increase in the expression of the lipogenic malic enzyme gene. Similar potentiating effects of NRTI and PI were observed on the expression of the fatty acid synthase gene.


CONCLUSIONS
Our data suggest that, like PI (although to a lesser extent) NRTI interfere with the differentiation process of adipocytes. In addition, we demonstrate that the effects produced by combinations of NRTI and PI are different from those elicited by each drug separately. This point may be particularly relevant in understanding the physiopathological mechanisms underlying the lipodystrophic syndrome.
Roche
Régis
R
INSERM Unit 476, School of Medicine of Marseilles, Marseilles, France.
Poizot-Martin
Isabelle
I
Yazidi
Claire Martin-El
CM
Compe
Emmanuel
E
Gastaut
Jean-Albert
JA
Torresani
Janine
J
Planells
Richard
R
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D004359:Drug Therapy, Combination; D008060:Lipodystrophy / Q000503:physiopathology; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D019380:Anti-HIV Agents; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D008291:Malate Dehydrogenase; D008071:Lipoprotein Lipase