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

Unit on Growth and Obesity (D.C.A.-W., N.F., J.A.Y.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development; Pulmonary-Critical Care Medicine Branch (H.L., F.A.,V.M.), National Heart, Lung, and Blood Institute; and Membrane Regulation Section (C.L.), Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Jack A. Yanovski, National Institutes of Health, Clinical Research Center, Room 1–3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892-1103. E-mail: jy15i{at}nih.gov.

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.

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