title: Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy.
abstract: HIV-1-infected patients may develop lipodystrophy and insulin resistance. We investigated the effect of the HIV-1 accessory protein viral protein R (Vpr) on the activity of the peroxisome proliferator-activating receptor-gamma (PPARgamma), a key regulator of adipocyte differentiation and tissue insulin sensitivity. We studied expression of PPARgamma-responsive reporter genes in 3T3-L1 mouse adipocytes. We investigated Vpr interaction with the PPAR/retinoid X receptor (RXR)-binding site of the c-Cbl-associating protein (CAP) gene using the chromatin immunoprecipitation assay as well as the interaction of Vpr and PPARgamma using coimmunoprecipitation. Finally, we studied the ability of exogenous Vpr protein to enter cultured adipocytes and retard differentiation. We found that Vpr suppressed PPARgamma-induced transactivation in both undifferentiated and differentiated 3T3-L1 cells. Transcriptional suppression by Vpr required an intact LXXLL coactivator motif. Vpr suppressed mRNA expression of PPARgamma-responsive genes in undifferentiated 3T3-L1 cells and associated with the PPAR/RXR-binding site located in the promoter region of the CAP gene. Vpr interacted with the ligand-binding domain of PPARgamma in an agonist-dependent fashion in vitro. Vpr delivered either by an expression plasmid or as protein added to media suppressed PPARgamma agonist-induced adipocyte differentiation, assessed as lipid accumulation and mRNA expression of the adipocyte differentiation marker adipocyte P2 in 3T3-L1 cells. In conclusion, circulating Vpr or, alternatively, Vpr produced as a consequence of direct infection of adipocytes could suppress in vivo differentiation of preadipocytes by acting as a corepressor of PPARgamma-mediated gene transcription. Vpr may alter sensitivity to insulin and thereby contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients.
authors.affiliation: Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease/NIH, 10 Center Drive MSC 1268, Bethesda, MD 20892-1268, USA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Shrivastav
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
authors.forename: Tshaka
authors.initials: T
authors.lastname: Cunningham
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ichijo
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schubert
authors.forename: Peter
authors.initials: P
authors.lastname: Heinklein
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016336:Gene Products, vpr / Q000235:genetics / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000235:genetics; D008060:Lipodystrophy / Q000378:metabolism / Q000821:virology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D016336:Gene Products, vpr; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D047488:Retinoid X Receptors