Effects of the human immunodeficiency virus-protease inhibitor, ritonavir, on basal and catecholamine-stimulated lipolysis.

Abstract

Several of the aspartic acid protease inhibitors used to treat HIV infection increase basal lipolysis in adipocytes, but the cellular mechanisms leading to this augmentation are not well understood. We therefore studied the effects of chronic exposure to the HIV protease inhibitor, ritonavir, on the lipolytic cascade in 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with ritonavir for 14 d (during and after differentiation) enhanced basal, isoproterenol (Iso)-stimulated, and cAMP analog-stimulated lipolysis. Enhancement of lipolysis was observed after Iso at concentrations between 0.1 and 10 mum. Despite a significant decrease in cyclic nucleotide phosphodiesterase (PDE)3B activity and protein levels, there were no changes in Iso-stimulated intracellular cAMP, protein kinase A (PKA) expression, or PKA activity. Ritonavir-augmented lipolysis was also observed under conditions that reversed the effect on PDE3B activity via preincubation with 1 mum (-)-N(6)-(2-phenylisopropyl)adenosine. In ritonavir-treated cells, protein expression of the lipid droplet-protective protein, perilipin, was significantly decreased, whereas there was no change in hormone-sensitive lipase. Activation of ERK1/2 by Iso did not play a role in the augmentation. We conclude that ritonavir decreases PDE3B and perilipin protein expression and affects both basal and catecholamine-stimulated lipolysis in 3T3-L1 adipocytes primarily through actions at sites downstream of PKA.

• Authors: Diane C Adler-Wailes, Hanguan Liu, Faiyaz Ahmad, Ningping Feng, Constantine Londos, Vincent Manganiello, Jack A Yanovski
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 90 Issue 6 Pg. 3251-61 (Jun 2005) ISSN: 0021-972X [Print] United States
• PMID: 15741249 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• HIV Protease Inhibitors
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 3
• PDE3B protein, human
• Pde3b protein, mouse
• Isoproterenol
• Ritonavir

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (metabolism)
• 3T3 Cells
• Adipocytes (cytology, drug effects, physiology)
• Animals
• Cell Differentiation
• Cyclic AMP (physiology)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 3
• HIV Protease Inhibitors (pharmacology)
• Isoproterenol (pharmacology)
• Lipolysis (drug effects)
• Mice
• Ritonavir (pharmacology)