Effects of the human immunodeficiency virus-protease inhibitor, ritonavir, on basal and catecholamine-stimulated lipolysis.
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.
Adler-Wailes
Diane C
DC
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Liu
Hanguan
H
Ahmad
Faiyaz
F
Feng
Ningping
N
Londos
Constantine
C
Manganiello
Vincent
V
Yanovski
Jack A
JA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D019438:Ritonavir / Q000494:pharmacology*
D017320:HIV Protease Inhibitors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517291:PDE3B protein, human; C517293:Pde3b protein, mouse; D007545:Isoproterenol; D019438:Ritonavir
Clin Infect Dis. 2000 Jun;30 Suppl 2:S160-70
10860901
J Biol Chem. 2000 Jul 7;275(27):20251-4
10806189
Arch Intern Med. 2000 Jul 10;160(13):2050-6
10888979
Annu Rev Nutr. 2000;20:365-93
10940339
Antiviral Res. 2000 Aug;47(2):121-9
10996400
Prog Nucleic Acid Res Mol Biol. 2001;66:241-77
11051766
Nat Genet. 2000 Dec;26(4):474-9
11101849
J Biol Chem. 2000 Dec 29;275(52):41325-32
11018036
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6494-9
11371650
Antivir Ther. 2003 Oct;8(5):417-26
14640389
J Biol Chem. 2003 Dec 19;278(51):51535-42
14527948
Diabetes. 2004 May;53(5):1261-70
15111495
J Clin Endocrinol Metab. 2004 Jul;89(7):3554-60
15240645
Mol Endocrinol. 2004 Sep;18(9):2123-31
15243132
J Biol Chem. 2004 Oct 1;279(40):42062-71
15292255
Endocrinology. 2004 Nov;145(11):4940-7
15284193
Nature. 1970 Aug 15;227(5259):680-5
5432063
J Cyclic Nucleotide Res. 1979;5(1):65-74
220290
J Clin Invest. 1995 Jun;95(6):2652-61
7769105
J Biol Chem. 1995 Jul 14;270(28):16970-3
7622516
J Biol Chem. 1997 Mar 14;272(11):6823-6
9102399
J Lipid Res. 1997 Nov;38(11):2249-63
9392423
N Engl J Med. 1998 Mar 26;338(13):853-60
9516219
Lancet. 1998 Mar 21;351(9106):871-5
9525365
AIDS. 1998 May 7;12(7):F51-8
9619798
Annu Rev Biophys Biomol Struct. 1998;27:249-84
9646869
Lancet. 1998 Jun 20;351(9119):1881-3
9652687
Lancet. 1998 Sep 26;352(9133):1032
9759749
Pharmacotherapy. 1999 Jan;19(1):35-59
9917077
J Biol Chem. 1999 Apr 23;274(17):12017-22
10207024
Anal Biochem. 1983 Jun;131(2):538-47
6193739
J Biol Chem. 1984 Mar 25;259(6):3539-47
6323428
J Biol Chem. 1985 Dec 5;260(28):15122-9
2415513
J Biol Chem. 1985 Dec 15;260(29):15781-8
2999137
Am J Physiol. 1987 Mar;252(3 Pt 1):C342-8
3030132
Anal Biochem. 1989 Jul;180(1):11-6
2817333
J Pharmacol Exp Ther. 1990 Apr;253(1):221-9
2158543
J Biol Chem. 1991 Jun 15;266(17):11341-6
2040638
Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12035-9
7505452
Lancet. 1999 Jun 19;353(9170):2093-9
10382692
J Biol Chem. 1957 May;226(1):497-509
13428781
Antivir Ther. 2004 Dec;9(6):911-20
15651750
J Biol Chem. 2005 Jan 21;280(3):2238-43
15525648
AIDS. 1999 Nov 12;13(16):2251-60
10563710
AIDS. 1999 Nov 12;13(16):2261-7
10563711
J Clin Endocrinol Metab. 1999 Nov;84(11):4274-7
10566684
Diabetes Metab. 1999 Nov;25(5):383-92
10592860
Biochim Biophys Acta. 2000 Jan 17;1483(2):251-62
10634941
Biochem J. 2000 Mar 1;346 Pt 2:337-43
10677351
Biochem Pharmacol. 2000 May 1;59(9):1063-8
10704935
Biochim Biophys Acta. 2000 Mar 7;1477(1-2):16-34
10708846
J Immunol. 2000 May 1;164(9):4678-88
10779773
Clin Infect Dis. 2000 Jun;30 Suppl 2:S135-42
10860898
Clin Infect Dis. 2000 Jun;30 Suppl 2:S151-9
10860900
Diabetes. 2001 Jun;50(6):1425-31
11375344
AIDS. 2001 Nov 9;15(16):2093-100
11684928
FASEB J. 2001 Nov;15(13):2527-9
11641262
J Biol Chem. 2001 Nov 30;276(48):45456-61
11581251
J Endocrinol. 2002 Jan;172(1):155-62
11786383
Metabolism. 2002 Feb;51(2):260-6
11833059
Diabetes. 2002 Mar;51(3):631-7
11872660
Lancet. 2002 Mar 23;359(9311):1026-31
11937183
J Biol Chem. 2002 May 31;277(22):19247-50
11937496
Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E332-7
12110539
Metabolism. 2002 Sep;51(9):1143-7
12200758
J Clin Endocrinol Metab. 2002 Nov;87(11):5066-71
12414873
J Clin Invest. 2002 Nov;110(9):1319-27
12417571
AIDS. 2003 Jan 3;17(1):23-32
12478066
J Lipid Res. 2003 Jan;44(1):103-8
12518028
Am J Clin Nutr. 2003 Feb;77(2):490-4
12540412
J Biol Chem. 2003 Mar 7;278(10):8401-6
12477720
J Cell Biol. 2003 Jun 23;161(6):1093-103
12810697
Int J Antimicrob Agents. 2003 Jul;22(1):54-9
12842328
Am J Physiol Endocrinol Metab. 2003 Sep;285(3):E490-7
12746213
Clin Infect Dis. 2003;37 Suppl 2:S47-51
12942374
J Endocrinol. 2003 Sep;178(3):449-56
12967347
AIDS. 2003 Oct 17;17(15):2177-80
14523274
J Biol Chem. 2003 Oct 31;278(44):43074-80
12941946