Effects of ritonavir on adipocyte gene expression: evidence for a stress-related response.
To understand the molecular mechanisms underlying the development of dyslipidemia and lipodystrophy that occurs after administration of aspartic acid protease inhibitors, we examined transcriptional profiles using cDNA microarrays in 3T3-L1 adipocytes exposed to 10 micromol/l ritonavir for 2-21 days. The expression levels of approximately 12,000 transcripts were assessed using the MgU74Av2 mouse microarray chip. Ritonavir altered gene expression of inflammatory cytokines, stress response genes localized to endoplasmic reticulum, oxidative stress genes, apoptosis-related genes, and expression of genes involved in cell adhesion and extracellular matrix remodeling. Microarray analysis also identified a novel gene downregulated by ritonavir, Cidea, whose expression levels may affect free-fatty acid metabolism. These changes suggest a unique, stress-related pattern in adipocytes induced by chronic exposure to the protease inhibitor, ritonavir.
Adler-Wailes
Diane C
DC
Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Guiney
Evan L
EL
Koo
Jashin
J
Yanovski
Jack A
JA
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D039682:HIV-Associated Lipodystrophy Syndrome / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
D016207:Cytokines; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D019438:Ritonavir