Comparison of the influence of four classes of HIV antiretrovirals on adipogenic differentiation: the minimal effect of raltegravir and atazanavir.
Antiretroviral therapy for HIV infection is associated with lipodystrophy. However, raltegravir (RAL), a new integrase inhibitor, and atazanavir (ATV), a new generation of protease inhibitor (PI), have not been reported to significantly induce metabolic abnormalities in some clinical studies. The aim of this study was to investigate the influence and molecular mechanisms of RAL and compared it with the other three classes of ARVs (nucleoside reverse-transcriptase inhibitors; NRTI, nonnucleoside reverse-transcriptase inhibitor; NNRTI, and PI) on adipogenesis using 3T3-L1 cells. RAL and ATV had minimal effects on the lipid metabolism of 3T3-L1 cells. NRTI induced a moderate change, and NNRTI and some PIs induced a severe reduction in cell lipid content. These ARVs induced a decrease in the expression of genes associated with lipogenic transcription factors (sterol regulatory-element-binding protein-1c, CAAT box enhancer-binding protein-α, and peroxisome proliferator-activated receptor-γ). The differentiated 3T3-L1 cells were less sensitive to ARV-induced metabolic disturbance than were predifferentiated cells. RAL and ATV did not significantly affect the lipid metabolism in our in vitro study. The other ARVs had a direct influence on adipocytes. Degree and underlying mechanisms of metabolic disturbance differed among different ARVs. These data suggest that the distinct metabolic side-effect profiles of ARVs are a consequences of their differential effects on the adipocyte physiology. A better understanding of the mechanism of ARV-induced metabolic abnormalities could lead to safer use of ARVs or selection of alternative agents for further clinical development.
Minami
Rumi
R
Internal Medicine, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, 810-8563, Japan. rrhh@kyumed.jp
Yamamoto
Masahiro
M
Takahama
Soichiro
S
Ando
Hitoshi
H
Miyamura
Tomoya
T
Suematsu
Eiichi
E
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D019380:Anti-HIV Agents / Q000145:classification / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D002454:Cell Differentiation / Q000187:drug effects*; D005786:Gene Expression Regulation; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress; D011725:Pyridines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D000068898:Raltegravir Potassium; D000069446:Atazanavir Sulfate