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.Highly active antiretroviral therapy (HAART) combines various protease inhibitors (PIs), nucleoside analogue reverse transcriptase inhibitors (NRTIs), and nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs). Whereas HAART efficiently suppresses human immunodeficiency virus (HIV) replication, long-term treatment of HIV-infected patients has been associated with a lipodystrophic syndrome and metabolic complications, with one of the most common complications being hypertriglyceridemia (6). The HAART-associated lipodystrophy is characterized by peripheral fat wasting in the face and limbs and the accumulation of visceral fat, breast hypertrophy, and cervical fat pads (buffalo hump) (7-9). Metabolic complications are preferentially associated with PI treatment and appear much more rapidly than lipodystrophy (20). It is not known whether the latter is a long-term consequence of the metabolic disorder or whether it corresponds to distinct molecular mechanisms. Because of the lack of a pertinent experimental model, the pathogenesis and physiopathological mechanisms by which PIs, NRTIs, and NNRTIs cause HAARTassociated lipodystrophy and metabolic disorders remain to be elucidated.PIs, NRTIs, and NNRTIs can interfere with adipocyte differentiation and adipocyte-specific gene expression (16,18,22,(26)(27)(28)(29). However, the reported effects are quite variable, positive or negative, depending on the molecule and on the experimental model studied. Furthermore, these cellular studies do not explain why HAART leads, in one case, to peripheral lipoatrophy and, in the other case, to abdominal...

Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration

“…For our study, there was a trend that showed PI treatment attenuated retroperitoneal fat pad mass compared to the other groups. This correlates with results from others who found significantly reduced retroperitoneal fat pad mass in mice treated with Ritonavir/Lopinavir [36,37]. It has been suggested that this may be linked to PI-mediated lowering of dietary intake in rodents [36,37], although this would need to be assessed in our model to determine whether indeed the case.…”

“…Similar findings were obtained following PI treatment of mice [36,37] and also within the clinical setting, e.g. the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) demonstrated lipoatrophy in HIV-infected men [38].…”

Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential

“…Murine clearance of LPV/RTV was substantial as little if any LPV could be detected in the mouse serum 8-h post-administration. 37 This prompted us to administer the drugs twice daily, with a minimum interval of 8 h. The LPV/RTV dosage had to be in the range of prescriptions established for humans and appropriate for a long-term treatment of mice. The chosen LPV dose was thus below that recapitulating the drug impregnation similar to the pattern observed in humans 37 (i.e., causing unwanted secondary effects).…”

The Role of Protease Inhibitors in the Pathogenesis of HIV-Associated Lipodystrophy: Cellular Mechanisms and Clinical Implications

“…We propose that inhibition of adipose glucose uptake by protease inhibitors is an early and important factor predisposing patients to lipoatrophy as well as peripheral insulin resistance. Clearly, additional factors are required for lipoatrophy to develop; especially important among these factors is treatment with NRTIs (Buffet et al 2005; Mallon et al 2003), but the direct association of PIs with white adipose tissue loss has been confirmed both clinically (Dube et al 2005; Heath et al 2002) and preclinically in the mouse (Prot et al 2006). …”