title: Long-term treatment with lopinavir-ritonavir induces a reduction in peripheral adipose depots in mice.
abstract: 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.
authors.affiliation: INSERM U568, Nice, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Prot
authors.forename: Laurence
authors.initials: L
authors.lastname: Heripret
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cardot-Leccia
authors.forename: Christophe
authors.initials: C
authors.lastname: Perrin
authors.forename: Myriam
authors.initials: M
authors.lastname: Aouadi
authors.forename: Thibaud
authors.initials: T
authors.lastname: Lavrut
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Garraffo
authors.forename: Pierre
authors.initials: P
authors.lastname: Dellamonica
authors.forename: Jacques
authors.initials: J
authors.lastname: Durant
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Bernard
authors.initials: B
authors.lastname: Binétruy
mesh_terms: 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
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D012333:RNA, Messenger; D014280:Triglycerides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019438:Ritonavir