The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Poster Session 81: Mechanisms Responsible for Metabolic Complications of Antiretroviral Therapy
February 3, 1999
Abstract No. 665: Indinavir Enhances Retinoic Acid Signaling: Nelfinavir, Saquinavir, and Ritonavir Inhibit Retinoid Effects in vitro
Authored by J.M. Lenhard, J.E. Weiel, M.A. Paulik, J.M. Lehmann, G. Kozalka, and E.S. Furfine
Lenhard et al (abstract 665) set out to to test the effects of PIs on a retinoic acid responsive gene (alkaline phosphatase in C3H10T1/2 preadipocyte cells), and discovered that not all protease inhibitors behaved similarly in this enzyme system. Essentially, indinavir was shown to increase the activity of this retinoid-dependent enzyme, in contrast to the inhibitory effects of nelfinavir, saquinavir and ritonavir. Amprenavir, on the other hand, had no effect. Whether these in vitro effects translate to the clinical effects of dyslipidemia in real patients remain to be seen. The work, however, serves to demonstrate an alteration in retinoid signaling as proposed by Carr et al, and to suggest that not all protease inhibtors have the same signaling effect.
Authored by J.M. Lenhard, J.E. Weiel, M.A. Paulik, L. Miller, O. Ittoop, S.G. Blanchard, and E.S. Furfine
In poster 666, Lenhard et al seek out the effects of protease inhibitors on adipocyte (the cells that store fat) metabolism and retinoid receptor signaling pathways (RXR and PPARgamma) in vitro. Alterations in adipocyte size and number may contribute to changes fat tissue mass and distribution (for example, lipodystrophy). Furthemore, after treatment with insulin, adipocyte size increases as a result of increased triglyceride synthesis in the cell (lipogenesis) and decresed lipid breakdown (lipolysis). Adipocyte numbers are influenced by agents that affect transition of stem cells into adipocytes (a process called adipogenesis), and this process is controlled by two nuclear receptors: PPARgamma, and RXRalpha. Agents like insulin, rexinoids and thiazolidiniones stimulate adipogenesis in vitro.
Their work demonstrated that saquinavir, nelfinavir and ritonavir prevented differentiation of stem cells into adipocytes, while inhibiting lipogenesis and stimulating lipolysis in existing adipocytes. Except for saquinavir, these effects were not due to binding of the PI to the PPAR or RXR receptors, but rather due to some other signaling effect via these receptors. Also, amprenavir and indinavir had little effect on adipogenesis in this model, suggesting that there is not a class-specific effect of PIs on fat metabolism in vitro.
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