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10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV6-8 November 2008, London, UK |
HIV PROTEASE INHIBITORS DIFFERENTLY AFFECT HUMAN SUBCUTANEOUS AND VISCERAL FAT: THEY INDUCE IL-6 PRODUCTION AND ALTER LIPID STORAGE CAPACITY IN SUBCUTANEOUS BUT NOT VISCERAL ADIPOSE TISSUE EXPLANTS
Antiviral Therapy 2008; 13(Suppl. 4):A3 (abstract no. O-02)
C Vatier1,2, S Leroyer1,2, J Quette1,2, N Brunel3, J Capeau1,2 and B Antoine1,2
1Inserm, UMR_S893, Paris, France; 2UPMC Univ Paris, UMR_S893, Faculté de Médecine Pierre et Marie Curie, Paris, France; 3Inserm, UPMC Univ Paris, Paris, France
OBJECTIVES: Antiretroviral therapy (ART)-related lipoatrophy is associated with a chronic low grade adipose tissue inflammation and an increased local production of interleukin (IL)-6. ART is also associated with a chronic excess of circulating fatty acids, which could account for increased liver triglyceride production and promote the development of an insulin resistant state. We have previously identified in human adipose tissue a new adipocyte lipid metabolic pathway, glyceroneogenesis, that participates during lipolysis in the recycling of fatty acids towards triglycerides. Mice invalidated in adipose tissue for its key enzyme, phosphoenol pyruvatecarboxykinase (PEPCK-c), present smaller adipose tissue depots together with increased systemic concentration of fatty acids. Thus, we wondered whether ART could affect glyceroneogenesis in human adipose tissue and whether increased IL-6 production could be related to altered lipid metabolism. As the ART-related lipodystrophic syndrome differentially affects subcutaneous and visceral fat depots, we comparatively studied the effect of ART in both.
METHODS: Human adipose tissue explants from abdominal subcutaneous (SCAT) and visceral depots (VAT) were recovered from non-HIV-infected lean women during gynaecologic surgery. They were treated ex vivo with 10 mM of stavudine, nelfinavir, lopinavir or ritonavir. Glycerol, fatty acids and cytokines secretion were quantified in the culture medium. Fatty acids re-esterification by glyceroneogenesis, PEPCK-c enzyme activity and gene expression (by real-time reverse transcriptase-PCR) were evaluated in the explants.
RESULTS: We observed that the three protease inhibitors (PIs), but not stavudine, increased fatty acid efflux from SCAT in the lipolytic situation. This effect was related to a PI-induced decreased efficiency of fatty acid re-esterification by glyceroneogenesis. Importantly, this effect was observed in SCAT but was absent in VAT. Accordingly, the different PIs were able to increase IL-6 gene expression and secretion in SCAT while they had no effect on these parameters in VAT. We then evaluated whether IL-6 overproduction could be responsible for altered lipid storage. We observed that IL-6 was able to decrease PEPCK-C enzyme activity. To further confirm that glyceroneogenesis is affected by PI-induced inflammation of SCAT, we showed that the addition of an anti-inflammatory agent inhibiting the NF-κB pathway (parthenolide) to nelfinavir prevented both IL-6 gene activation and PEPCK-C gene inhibition induced by the PI.
CONCLUSIONS: Our results show, that some PIs induce an inflammatory profile in human SCAT as indicated by increased IL-6 production. This resulted in decreased fatty acid re-esterification through the glyceroneogenesis pathway and increased fatty acid release. These alterations could help to understand the ART-related SCAT lipoatrophy and systemic hyperlipidaemy. Under similar conditions, VAT was resistant to the deleterious actions of PIs. These data are in accordance with the clinical discordant effect of ART in the two fat depots observed in HIV-related lipodystrophies.
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2008-11-06
O-02
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