HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through Recipr

HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through Reciprocal Effects on PPAR/GR Co-Regulation

HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through ReciprocalEffects on PPAR/GR Co-RegulationNeeti Agarwal et al.

Sci Transl Med 5, 213ra164 (2013);DOI: 10.1126/scitranslmed.3007148

Editor's Summary

Chewing the Fat with HIV Protein

HIV infection is infamously known for its devastating immunosuppressive effects; however, immunosuppressionis not the whole story. Patients whose viral load is well controlled with antiretroviral therapy (ART) are still at risk for a variety of chronic metabolic complications, including adipose dysfunction. ART drugs have been implicated in some ofthese chronic complications, but others, such as decreased body fat and altered fat distribution, occur in even untreated patients. Now, Agarwal et al. demonstrate that, at least in mice, the HIV protein viral protein R (Vpr) maydirectly contribute to adipose dysfunction.

Downloaded from http://www.77cn.com.cn on August 12, 2014

The authors began with the observation that Vpr circulates in the blood of HIV-infected patients on ART, even those with no detectable viral load. Paired with the knowledge that Vpr can coactivate the glucocorticoid receptor (GR)and co-repress peroxisome proliferator activated receptor γ (PPARγ), both of which are involved in metabolic

regulation, they hypothesized the Vpr itself may play a pathogenic role in adipose dysfunction in these individuals. They took their studies into two mouse models of Vpr expression that lacked HIV infection: transgenic and

pharmacologic. Vpr alone could disrupt PPAR/GR co-regulation and cell cycle control in adipose depots and liver to produce adipose dysfunction and hepatosteatosis. If these mechanisms hold true in humans, they could lead to

targeted treatment of these metabolic complications with Vpr inhibitors, GR antagonists, or PPARγ/PPARα agonists.

A complete electronic version of this article and other services, including high-resolution figures,can be found at:

http://www.77cn.com.cn/content/5/213/213ra164.full.html

Supplementary Material can be found in the online version of this article at: http://www.77cn.com.cn/content/suppl/2013/11/25/5.213.213ra164.DC1.html Related Resources for this article can be found online at:

http://www.77cn.com.cn/content/scitransmed/5/181/181ra51.full.html http://www.77cn.com.cn/content/scitransmed/4/123/123ra25.full.html http://www.77cn.com.cn/content/sci/343/6171/653.full.html

http://www.77cn.com.cn/content/sci/343/6177/1243727.full.html http://www.77cn.com.cn/content/sci/345/6196/570.full.html

Information about obtaining reprints of this article or about obtaining permission to reproduce thisarticle in whole or in part can be found at:

http://www.77cn.com.cn/about/permissions.dtl

Science Translational Medicine (print ISSN 1946-6234; online ISSN 1946-6242) is published weekly, except thelast week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2013 by the American Association for the Advancement of Science; allrights reserved. The title Science Translational Medicine is a registered trademark of AAAS.

HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through Reciprocal Effects on PPAR/GR Co-Regulation

HIV

HIV-1VprInducesAdiposeDysfunctioninVivo

ThroughReciprocalEffectsonPPAR/GRCo-Regulation

NeetiAgarwal,1*DinakarIyer,1*SanjeetG.Patel,1 RajagopalV.Sekhar,1,2TerryM.Phillips,3UlrichSchubert,4ToniOplt,1EricD.Buras,1 SusanL.Samson,1,2JacobCouturier,5DorothyE.Lewis,5MariaC.Rodriguez-Barradas,6FarookJahoor,7TomoshigeKino,3JeffreyB.Kopp,8AshokBalasubramanyam1,2§

Viralinfections,suchasHIV,havebeenlinkedtoobesity,butmechanisticevidencethattheycauseadiposedysfunctioninvivoislacking.WeinvestigatedapathogenicrolefortheHIV-1accessoryproteinviralproteinR(Vpr),whichcancoactivatetheglucocorticoidreceptor(GR)andco-repressperoxisomeproliferator–activatedreceptorg(PPARg)invitro,inHIV-associatedadiposedysfunction.VprcirculatedinthebloodofmostHIV-infectedpatientstested,includingthoseonantiretroviraltherapy(ART)withundetectableviralload.Vpr-mediatedmechanismsweredissectedinvivousingmousemodelsexpressingtheVprtransgeneinadiposetissuesandliver(Vpr-Tg)orinfusedwithsyntheticVpr.Bothmodelsdemonstratedacceleratedwhole-bodylipolysis,hyperglycemiaandhypertriglyceridemia,andtissue-specificfindings.Fatdepotsinthesemicehaddiminishedmass,macrophageinfiltration,andbluntedPPARgtargetgeneexpressionbutincreasedGRtargetgeneexpression.Inliver,weobservedbluntedPPARatargetgeneexpression,steatosiswithdecreasedadenosinemonophosphate–activatedproteinkinaseactivity,andinsulinresistance.SimilartohumanHIV-infectedpatients,VprcirculatedintheserumofVpr-Tgmice.Vprblockeddifferentiationinpreadipocytesthroughcellcyclearrest,whereasinmatureadipocytes,itincreasedlipolysiswithreciprocallyalteredassociationofPPARgandGRwiththeirtargetpromoters.Theseresultsdelineateadistinctpathogenicsequence:Vpr,releasedfromHIV-1intissuereservoirsafterART,candisruptPPAR/GRco-regulationandcellcyclecontroltoproduceadiposedysfunctionandhepatosteatosis.Confir-mationofthesemechanismsinHIVpatientscouldleadtotargetedtreatmentofthemetaboliccomplicationswithVprinhibitors,GRantagonists,orPPARg/PPARaagonists.

INTRODUCTION

Viralinfectionsarelinkedtoobesity(1)andfattyliver(2),butevi-dencethattheycauseadiposedysfunctioniscorrelative(3).Invivomechanismswherebyvirusesinduceadipocytedefectsinhumanad-iposedisordershavenotbeenreported.HIVpatientsmanifestadiposedysfunctioncharacterizedbyacceleratedlipolysis,lipoatrophyinsomedepotsandlipohypertrophyinothers,hepatosteatosis,dyslipidemia,insulinresistance,andhyperglycemia.Antiretroviraltherapy(ART)drugshavebeenimplicatedinsomeabnormalities(4).However,adverseeffectsofARTcannotexplainkeyaspectsofthephenot …… 此处隐藏：61242字，全部文档内容请下载后查看。喜欢就下载吧 ……