Effects of the Human Immunodeficiency Virus-Protease Inhibitor, Ritonavir, on Basal and Catecholamine-Stimulated Lipolysis

• Published in: The journal of clinical endocrinology and metabolism Vol. 90; no. 6; pp. 3251 - 3261
• Main Authors: Adler-Wailes, Diane C, Liu, Hanguan, Ahmad, Faiyaz, Feng, Ningping, Londos, Constantine, Manganiello, Vincent, Yanovski, Jack A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.06.2005
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; 3T3 Cells; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - physiology; Animals; Biological and medical sciences; Cell Differentiation; Cyclic AMP - physiology; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 3; Endocrinopathies; Fundamental and applied biological sciences. Psychology; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Isoproterenol - pharmacology; Lipolysis - drug effects; Medical sciences; Mice; Ritonavir - pharmacology; Vertebrates: endocrinology; Enzyme; Ritonavir; Enzyme inhibitor; Retroviridae; Catecholamine; Lentivirus; Lipolysis; Virus; Peptidases; Hydrolases; Human immunodeficiency virus; Endocrinology; Protease inhibitor
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2004-2194

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 μm. 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 μm (-)-N6-(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.