Long-term treatment with lopinavir-ritonavir induces a reduction in peripheral adipose depots in mice.
Highly active antiretroviral therapy (HAART) of human immunodeficiency virus-infected patients is associated with adverse effects, such as lipodystrophy and hyperlipidemia. The lipodystrophic syndrome is characterized by a peripheral lipoatrophy and/or fat accumulation in the abdomen and neck. In order to get insights into the physiopathological mechanisms underlying this syndrome, we treated mice with protease inhibitors (PIs) over a long period of time. Although atazanavir-treated mice presented the same circulating triglyceride concentration as control mice, lopinavir-ritonavir-treated mice rapidly became hypertriglyceridemic, with triglyceride levels of 200 mg/dl, whereas control and atazanavir-treated animals had triglyceride levels of 80 mg/dl. These results obtained with mice reproduce the metabolic disorder observed in humans. White adipose tissue (WAT) was analyzed after 8 weeks of treatment. Compared to the control or atazanavir treatment, lopinavir-ritonavir treatment induced a significant 25% weight reduction in the peripheral inguinal WAT depot. By contrast, the profound epididymal WAT depot was not affected. This effect was associated with a 5.5-fold increase in SREBP-1c gene expression only in the inguinal depot. Our results demonstrate that the long-term treatment of mice with PIs constitutes an interesting experimental model with which some aspects of the lipoatrophy induced by HAART in humans may be studied.
Prot
Matthieu
M
INSERM U568, Nice, France.
Heripret
Laurence
L
Cardot-Leccia
Nathalie
N
Perrin
Christophe
C
Aouadi
Myriam
M
Lavrut
Thibaud
T
Garraffo
Rodolphe
R
Dellamonica
Pierre
P
Durant
Jacques
J
Le Marchand-Brustel
Yannick
Y
Binétruy
Bernard
B
D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D000069446:Atazanavir Sulfate; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000209:etiology; D061466:Lopinavir; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D012333:RNA, Messenger; D014280:Triglycerides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019438:Ritonavir