Significant advances in the treatment of the morbidity and mortality associated with AIDS are also associated with undesirable side-effects in fat redistribution (lipodystrophy), insulin resistance and cardiovascular risk, which is directly linked to protease inhibitor (PI) treatment.
Methods
The effects of four different PIs on triglyceride (TG) storage and adipokine production (leptin, adiponectin, and acylation stimulating protein [ASP]) in omental (OM) and subcutaneous (SC) adipose tissues were examined.
Results
Initial results demonstrated that saquinivir (SQV) and ritonivir (RTV) had little observed effect on de novo TG synthesis ([3H]glucose incorporation into TG) or fatty acid re-esterification ([14C]oleate incorporation into TG), whereas amprenivir (APV) and indinivir (IDV) reduced TG synthesis, especially in SC tissue up to 30 ±5.8% P<0.05 and 46 ±7.8% P<0.001, at 20 μM, respectively. There was no observed effect on phospholipid synthesis, tissue protein or toxicity. Only APV and IDV decreased leptin and adiponectin secretion in SC tissue, in a time- and concentration-dependent manner: at 18 h, leptin was inhibited by 54 ±3.1% (P<0.001) and 44 ±6.4% (P<0.001) by APV and IDV (40 μM), respectively, and adiponectin was inhibited by 35 ±5.6%(P<0.001) and 25 ±12.3% (P<0.05) by APV and IDV (40 μM), respectively. By contrast, both IDV and APV decreased ASP secretion in OM tissues by a maximum of 53 ±7.8% (P<0.001) and 59 ±5.9% (P<0.001), respectively, and by a maximum of 86 ±1.6% (P<0.001) and 72 ±4% (P<0.001), respectively, in SC tissues.
Conclusion
PI have a direct effect on human adipose tissue which are site, PI and adipokine specific; these effects may contribute to the overall adipose imbalance and development of lipodystrophy, and metabolic syndrome in HIV-positive individuals.
References
1.
HuiD.Y.Effects of HIV protease inhibitor therapy on lipid metabolism.Prog Lipid Res2003; 42: 81–92.
2.
WankeC.A., FalutzG.M., PhairJ.P., KotlerD.P.Clinical evaluation and management of metabolic and morphologic abnormalities associated with human immunodeficiency virus.Clin Infect Dis2002; 34: 248–259.
LeeG.A., SeneviratneT., NoorM.A.The metabolic effects of lopinavir/ritonavir in HIV-negative men.AIDS2004; 18: 641–649.
5.
PurnellJ.Q., ZambonA., KnoppR.H.Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects.AIDS2000; 14: 51–57.
6.
LenhardJ.M., CroomD.K., WeielJ.E., SpaltensteinA., ReynoldsD.J., FurfineE.S.Dietary fat alters HIV protease inhibitor-induced metabolic changes in mice.J Nutr2000; 130: 2361–2366.
7.
RiddleT.M., KuhelD.G., WoollettL.A., FichtenbaumC.J., HuiD.Y.HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus.J Biol Chem2001; 276: 37514–37519.
8.
Ben-RomanoR., RudichA., TorokD., VanounouS., RiesenbergK., SchlaefferF.Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors.AIDS.200317: 23–32.
9.
Ben-RomanoR., RudichA., TiroshA., PotashnikR., SasaokaT., RiesenbergK.Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-zeta.Diabetologia2004; 47: 1107–1117.
10.
CaronM., AuclairM., SterlingotH., KornprobstM., CapeauJ.Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation.AIDS2003; 17: 2437–2444.
11.
ArnerP.Differences in lipolysis between human subcutaneous and omental adipose tissues.Ann Med1995; 27: 435–438.
12.
HavelP.J.Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism.Diabetes2004; 53 (Suppl 1): S143–S151.
13.
CianfloneK., XiaZ., ChenL.Y.Critical review of Acylation Stimulating Protein physiology in humans and rodents.Biochim Biophys Acta20031609: 127–143.
14.
ChaldakovG.N., StankulovI.S., HristovaM., GhenevP.I.Adipobiology of disease: adipokines and adipokine-targeted pharmacology.Curr Pharm Des2003; 9: 1023–1031.
ReidyS.P., WeberJ.Leptin: an essential regulator of lipid metabolism.Comp Biochem Physiol A Mol Integr Physiol2000; 125: 285–298.
17.
MaslowskaM., WangH.W., CianfloneK.Novel roles for Acylation Stimulating Protein (ASP)/C3adesArg: a review of recent in vitro and in vivo evidence.Vitam Horm2004; 70: 309–332.
18.
HavelP.J.Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin.Curr Opin Lipidol2002; 13: 51–59.
19.
YamauchiT., KamonJ., MinokoshiY.Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.Nat Med2002; 8: 1288–1295.
20.
SnidermanA.D., BrownB.G., StewartF.F., CianfloneK.From familial combined hyperlipidemia to hyperapoB: Unravelling overproduction of heptic apoB lipoproteins.Curr Opin Lipidol1992; 3: 137–142.
21.
Van HarkenD.R., DixonC.W., HeimbergM.Hepatic lipid metabolism in experimental diabetes. V. The effect of concentration of oleate on metabolism of triglycerides and on ketogenesis.J Biol Chem1969; 244: 2278–2285.
22.
TengB., ForseA., RodriguezM.A., SnidermanA.D.Adipose tissue glyceride synthesis in patients with hyperapobetalipoproteinemia.Can J Physiol Pharmacol1988; 66: 239–242.
23.
WalldiusG., RubbaP.A micromethod for determinarion of fatty acid (FIAT) and glucose (GLIAT) incorporation and lipolysis in vitro in needle biopsies of human adipose tissue.Scand J Clin Lab Invest1976; 36: 357–369.
24.
MaslowskaM., SnidermanA.D., MacLeanL.D., CianfloneK.Regional differences in triacylglycerol synthesis in adipose tissue.J Lipid Res1993; 34: 219–228.
25.
LeibelR.L., HirschJ.A radioisotopic technique for analysis of free fatty acid re-esterification in human adipose tissue.Am J Physiol1985; 248: E140–E147.
26.
BradfordM.M.A rapid and sensitive method for the quantitation of microgram quantities or protein utilizing the principal of protein-dye binding.Analyt Biochem197672: 248–254.
27.
SalehJ., SummersL.K.M., CianfloneK., FieldingB.A., SnidermanA.D., FraynK.N.Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J Lipid Res1998; 39: 884–891.
28.
ScantleburyT., MaslowskaM., CianfloneK.Chylomicron specific enhancement of Acylation Stimulating Protein (ASP) and precursor protein C3 production in differentiated human adipocytes.J Biol Chem1998; 273: 20903–20909.
29.
PanM., LiangJ.S., FisherE.A., GinsbergH.N.The late addition of core lipids to nascent apolipoprotein B100, resulting in the assembly and secretion of triglyceride-rich lipoproteins, is independent of both microsomal triglyceride transfer protein activity and new triglyceride synthesis.J Biol Chem2002; 277: 4413–4421.
30.
BrasaemleD.L., RubinB., HartenI.A., Gruia-GrayJ., KimmelA.R., LondosC.Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis.J Biol Chem2000; 275: 38486–38493.
31.
KotlerD.P., IonescuG., JohnsonJ.A.Albu. Studies of adipose tissue metabolism in human immunodeficiency virus-associated lipodystrophy.Clin Infect Dis2003; 37: S47–S51.
32.
JohnsonJ.A., AlbuJ.B., EngelsonE.S.Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy.Am J Physiol Endocrinol Metab2004; 286: E261–E271.
DowellP., FlexnerC., KwiterovichP.O., LaneM.D.Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors.J Biol Chem2000; 275: 41325–41332.
35.
BastardJ.P., CaronM., VidalH.Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance.Lancet2002359: 1026–1031.
36.
HadiganC., BorgonhaS., RabeJ., YoungV., and GrinspoonS.. Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy.Metabolism.200251: 1143–1147.
37.
HadiganC., RabeJ., MeiningerG., AliabadiN., BreuJ., GrinspoonS.Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution.Am J Clin Nutr2003; 77: 490–494.
SutinenJ., KorsheninnikovaE., FunahashiT., MatsuzawaY., NymanT., Yki-JarvinenH.Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy.J Clin Endocrinol Metab2003; 88: 1907–1910.
40.
AddyC.L., GavrilaA., TsiodrasS., BrodoviczK., KarchmerA.W., MantzorosC.S.Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy.J Clin Endocrinol Metab2003; 88: 627–636.
41.
KosmiskiL., KuritzkesD., LichtensteinK., EckelR.Adipocyte-derived hormone levels in HIV lipodystrophy.Antivir Ther2003; 8: 9–15.
42.
VigourouxC., MaachiM., NguyenT.H.Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy.AIDS2003; 17: 1503–1511.
43.
CarrA., SamarasK., BurtonS., LawM., ChisholmD.J., CooperD.A.A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.AIDS199812: F51–F58.
44.
IonescuG., KotlerD.P., EngelsonE.S., AginD., InadaY.Serum complement components in HIV-infected individuals with and without fat redistribution (lipodystrophy).J Acquir Immune Defic Syndr2000; 25: 370–371.
45.
SnidermanA.D., ScantleburyT., CianfloneK.Hypertriglyceridemia HyperapoB: The unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus.Ann Intern Med2001; 135: 447–459.
46.
CarrA., SamarasK., ChisholmD.J., CooperD.A.Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.Lancet1998351: 1881–1883.
SchneiderW.J., NimpfJ.LDL receptor relatives at the crossroad of endocytosis and signaling.Cell Mol Life Sci2003; 60: 892–903.
49.
HerzJ., StricklandD.K.LRP: a multifunctional scavenger and signaling receptor.J Clin Invest2001; 108: 779–784.
50.
MeilingerM., GschwentnerC., BurgerI.Metabolism of activated complement component C3 is mediated by the low density lipoprotein receptor-related protein/a2-Macroglobulin receptor.J Biol Chem1999; 274: 38091–38096.
