HIV-1 Tat protein has been shown to play multiple roles in the pathogenesis of AIDS; however, there is no information currently available on its effects on adipose tissue alterations. We have studied the effects of Tat on SGBS adipocytes to gain insight on its role on the development of lipodystrophy.
Methods
SGBS preadipocytes were exposed to Tat during and after differentiation. Acquisition of adipocyte morphology, expression of gene markers of adipogenesis and inflammation, release of adipokines and cytokines to the medium, and glucose uptake were measured. The action of Tat on tumour necrosis factor (TNF)-α-regulated messenger RNA expression was determined in differentiated adipocytes. The capacity of rosiglitazone, resveratrol and parthenolide to influence the action of Tat was also assessed.
Results
Tat treatment reduced the number of SGBS preadipocytes that acquired adipocyte morphology. It also led to repression of adipogenic gene expression and induced the coordinate expression and release of proinflammatory cytokines in human adipose cells. Moreover, combined treatment with Tat and TNF-α produced an additive effect on the repression of adipocyte genes. The observed effects of Tat on gene transcription in adipocytes were due, in part, to TNF-α that was secreted as a consequence of intracellular exposure to Tat.
Conclusions
Tat impairs adipogenesis in human SGBS preadipocytes and increases the expression and release of proinflammatory cytokines. Positive crosstalk between Tat and TNF-α contributes to the anti-adipogenic and proinflammatory effects. HIV-1 Tat protein may play a role in the adipose tissue alterations that ultimately lead to lipoatrophy and systemic metabolic disturbances observed in HIV-1-infected patients.
References
1.
Caron-DebarleM., LagathuC., BoccaraF., VigourouxC., CapeauJ.HIV-associated lipodystrophy: from fat injury to premature aging. Trends Mol Med2010; 16: 218–229.
2.
VillarroyaF., DomingoP., GiraltM.Lipodystrophy in HIV 1-infected patients: lessons for obesity research. Int J Obes (Lond)2007; 31: 1763–1776.
3.
BoydM.A., DixitN.M., SiangphoeU.Viral decay dynamics in HIV-infected patients receiving ritonavir-boosted saquinavir and efavirenz with or without enfuvirtide: a randomized, controlled trial (HIV-NAT 012). J Infect Dis2006; 194: 1319–1322.
4.
FlintO.P., NoorM.A., HruzP.W.The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol Pathol2009; 37: 65–77.
5.
VisnegarwalaF., RaghavanS.S., MullinC.M.Sex differences in the associations of HIV disease characteristics and body composition in antiretroviral-naive persons. Am J Clin Nutr2005; 82: 850–856.
6.
GiraltM., DomingoP., GuallarJ.P.HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV- 1/HAART-associated lipodystrophy. Antivir Ther2006; 11: 729–740.
7.
HazanU., RomeroI.A., CancelloR.Human adipose cells express CD4, CXCR4, and CCR5 receptors: a new target cell type for the immunodeficiency virus-1?FASEB J2002; 16: 1254–1256.
8.
DupinN., BuffetM., MarcelinA.G.HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. AIDS2002; 16: 2419–2424.
9.
MunierS., BorjabadA., LemaireM., MariotV., HazanU.In vitro infection of human primary adipose cells with HIV-1: a reassessment. AIDS2003; 17: 2537–2539.
10.
MaurinT., Saillan-BarreauC., CousinB., CasteillaL., DoglioA., PénicaudL.Tumor necrosis factor-alpha stimulates HIV-1 production in primary culture of human adipocytes. Exp Cell Res2005; 304: 544–551.
11.
ShrivastavS., KinoT., CunninghamT.Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor-γ and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy. Mol Endocrinol2008; 22: 234–247.
12.
RomaniB., EngelbrechtS., GlashoffR.H.Functions of Tat: the versatile protein of human immunodeficiency virus type 1. J Gen Virol2010; 91: 1–12.
13.
LaspiaM.F., RiceA.P., MathewsM.B.HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation. Cell1989; 59: 283–292.
14.
EnsoliB., BuonaguroL., BarillariG.Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol1993; 67: 277–287.
15.
ChangH.C., SamaniegoF., NairB.C., BuonaguroL., EnsoliB.HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS1997; 11: 1421–1431.
16.
WestendorpM.O., FrankR., OchsenbauerC.Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature1995; 375: 497–500.
17.
XiaoH., NeuveutC., TiffanyH.L.Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci U S A2000; 97: 11466–11471.
18.
JuS.M., SongH.Y., LeeJ.A., LeeS.J., ChoiS.Y., ParkJ.Extracellular HIV-1 Tat up-regulates expression of matrix metalloproteinase-9 via a MAPK-NF-kappaB dependent pathway in human astrocytes. Exp Mol Med2009; 41: 86–93.
19.
BennasserY., BahraouiE.HIV-1 Tat protein induces interleukin-10 in human peripheral blood monocytes: involvement of protein kinase C-βII and -δ. FASEB J2002; 16: 546–554.
20.
ChenP., MayneM., PowerC., NathA.The Tat protein of HIV-1 induces tumor necrosis factor-α production: implications for HIV-1-associated neurological diseases. J Biol Chem1997; 272: 22385–22388.
21.
CuppC., TaylorJ.P., KhaliliK., AminiS.Evidence for stimulation of the transforming growth factor beta1 promoter by HIV-1 Tat in cells derived from CNS. Oncogene1993; 8: 2231–2236.
22.
LiJ.C., YimH.C., LauA.S.Role of HIV-1 Tat in AIDS pathogenesis: its effects on cytokine dysregulation and contributions to the pathogenesis of opportunistic infection. AIDS2010; 24: 1609–1623.
23.
WabitschM., BrennerR.E., MelznerI.Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes Relat Metab Disord2001; 25: 8–15.
24.
CampbellG.R., LoretE.P.What does the structure-function relationship of the HIV-1 Tat protein teach us about developing an AIDS vaccine?Retrovirology2009; 6: 50.
25.
HayashiK., PuH., AndrasI.E.HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier. J Cereb Blood Flow Metab2006; 26: 1052–1065.
26.
ToborekM., LeeY.W., PuH.HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J Neurochem2003; 84: 169–179.
27.
AndrásI.E., PuH., DeliM.A., NathA., HennigB., ToborekM.HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J Neurosci Res2003; 74: 255–265.
28.
LeeY.W., EumS.Y., NathA., ToborekM.Estrogen-mediated protection against HIV Tat protein-induced inflammatory pathways in human vascular endothelial cells. Cardiovasc Res2004; 63: 139–148.
29.
NathA., ConantK., ChenP., ScottC., MajorE.O.Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem1999; 274: 17098–17102.
30.
DoM.S., JeongH.S., ChoiB.H.Inflammatory gene expression patterns revealed by DNA microarray analysis in TNF-alpha-treated SGBS human adipocytes. Yonsei Med J2006; 47: 729–736.
31.
LehmannJ.M., MooreL.B., Smith-OliverT.A., WilkisonW.O., WillsonT.M., KliewerS.A.An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem1995; 270: 12953–12956.
32.
YoshizakiT., MilneJ.C., ImamuraT.SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol2009; 29: 1363–1374.
KwokB.H., KohB., NdubuisiM.I., ElofssonM., CrewsC.M.The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol2001; 8: 759–766.
35.
MayolK., MunierS., BeckA., VerrierB., GuillonC.Design and characterization of an HIV-1 Tat mutant: inactivation of viral and cellular functions but not antigenicity. Vaccine2007; 25: 6047–6060.
36.
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.
37.
RangwalaS.M., LazarM.A.Peroxisome proliferator-activated receptor γ in diabetes and metabolism. Trends Pharmacol Sci2004; 25: 331–336.
38.
GougeonM.L., PénicaudL., FromentyB., LeclercqP., ViardJ.P., CapeauJ.Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations. Antivir Ther2004; 9: 161–177.
39.
LagougeM., ArgmannC., Gerhart-HinesZ.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell2006; 127: 1109–1122.
40.
BaurJ.A., PearsonK.J., PriceN.L.Resveratrol improves health and survival of mice on a high-calorie diet. Nature2006; 444: 337–342.
41.
TouzetO., PhilipsA.Resveratrol protects against protease inhibitor-induced reactive oxygen species production, reticulum stress and lipid raft perturbation. AIDS2010; 24: 1437–1447.
42.
PagansS., PedalA., NorthB.J.SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol2005; 3: e41.
43.
PicardF., KurtevM., ChungN.Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature2004; 429: 771–776.
44.
FloydZ.E., WangZ.Q., KilroyG., CefaluW.T.Modulation of peroxisome proliferator-activated receptor gamma stability and transcriptional activity in adipocytes by resveratrol. Metabolism2008; 57Suppl 1: S32–S38.
45.
LeeE.O., KimS.E., ParkH.K.Extracellular HIV-1 Tat upregulates TNF-α dependent MCP-1/CCL2 production via activation of ERK1/2 pathway in rat hippocampal slice cultures: inhibition by resveratrol, a polyphenolic phytostilbene. Exp Neurol2011; 229: 399–408.
46.
GhoshS., MayM.J., KoppE.B.NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol1998; 16: 225–260.
47.
OttM., LovettJ.L., MuellerL., VerdinE.Superinduction of IL-8 in T cells by HIV-1 Tat protein is mediated through NF-kB factors. J Immunol1998; 160: 2872–2880.
48.
ConantK., MaM., NathA., MajorE.O.Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kB binding and protein kinase C activity in primary human astrocytes. J Virol1996; 70: 1384–1389.
49.
LeeY.W., HiraniA.A., KyprianouN., ToborekM.Human immunodeficiency virus-1 Tat protein up-regulates interleukin-6 and interleukin-8 expression in human breast cancer cells. Inflamm Res2005; 54: 380–389.
50.
GandhiN., SaiyedZ., ThangavelS., RodriguezJ., RaoK.V., NairM.P.Differential effects of HIV type 1 clade B and clade C Tat protein on expression of proinflammatory and antiinflammatory cytokines by primary monocytes. AIDS Res Hum Retroviruses2009; 25: 691–699.
