Drug-specific effect of nelfinavir and stavudine on primary culture of human preadipocytes.
Lipodystrophic syndrome is a major side effect of antiviral therapy leading to profound disturbances in adipose tissue. Human preadipocyte primary culture represents a model to understand mechanisms by which antiretroviral drugs alter adipocyte biology. The aim of this study was to evaluate the effects of various protease and nucleoside reverse transcriptase inhibitors in this model. We tested the effect of drugs on triglyceride accumulation and expression of specific genes by real-time polymerase chain reaction. To determine differential mechanisms by which the efficient drugs operate, we studied mitochondrial effects by evaluating oxygen consumption rates and nuclear lamina alteration by immunocytology. Only stavudine and nelfinavir, both at 10 microM, altered human adipose cell differentiation, as shown by reduced triglyceride accumulation. Our studies revealed that stavudine increased expression of genes such as PGC1 and LPL and affected mitochondrial respiration. Cells treated with nelfinavir had a lower expression of PPARgamma, LPL, and ap2 and presented disorganization of lamin A/C. Our data suggest for the first time in a model of human adipocytes differentiated in vitro that stavudine and nelfinavir interfere with the process of differentiation by 2 distinct mechanisms. This may be particularly relevant in understanding the physiopathologic mechanisms underlying the lipodystrophic syndrome.
Saillan-Barreau
Corinne
C
Mitochondrie, Plasticité, Métabolisme, Université Paul Sabatier, Toulouse, France.
Tabbakh
Oumaima
O
Chavoin
Jean-Pierre
JP
Casteilla
Louis
L
Pénicaud
Luc
L
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects*; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D017931:DNA Primers; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019888:Nelfinavir / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology*
D017931:DNA Primers; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D019888:Nelfinavir