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

Shashi Shrivastav, Tomoshige Kino, Tshaka Cunningham, Takamasa Ichijo, Ulrich Schubert, Peter Heinklein, George P. Chrousos, Jeffrey B. Kopp

Research output: Contribution to journalArticle

57 Citations (Scopus)

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-γ (PPARγ), a key regulator of adipocyte differentiation and tissue insulin sensitivity. We studied expression of PPARγ-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 PPARγ using coimmunoprecipitation. Finally, we studied the ability of exogenous Vpr protein to enter cultured adipocytes and retard differentiation. We found that Vpr suppressed PPARγ-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 PPARγ-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 PPARγ in an agonist-dependent fashion in vitro. Vpr delivered either by an expression plasmid or as protein added to media suppressed PPARγ 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 PPARγ-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.

Original languageEnglish
Pages (from-to)234-247
Number of pages14
JournalMolecular Endocrinology
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 2008
Externally publishedYes

Fingerprint

vpr Gene Products
Lipodystrophy
Peroxisome Proliferator-Activated Receptors
Peroxisome Proliferators
Adipocytes
HIV-1
HIV
3T3-L1 Cells
Insulin Resistance
Retinoid X Receptors
Proto-Oncogene Proteins c-cbl
Proteins
Binding Sites
Genes
Co-Repressor Proteins
Messenger RNA
Chromatin Immunoprecipitation
Differentiation Antigens
Reporter Genes
Genetic Promoter Regions

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

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. / Shrivastav, Shashi; Kino, Tomoshige; Cunningham, Tshaka; Ichijo, Takamasa; Schubert, Ulrich; Heinklein, Peter; Chrousos, George P.; Kopp, Jeffrey B.

In: Molecular Endocrinology, Vol. 22, No. 2, 02.2008, p. 234-247.

Research output: Contribution to journalArticle

Shrivastav, Shashi ; Kino, Tomoshige ; Cunningham, Tshaka ; Ichijo, Takamasa ; Schubert, Ulrich ; Heinklein, Peter ; Chrousos, George P. ; Kopp, Jeffrey B. / 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. In: Molecular Endocrinology. 2008 ; Vol. 22, No. 2. pp. 234-247.
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