help button home button Endocrine Society Molecular Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on October 11, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0124
A more recent version of this article appeared on February 1, 2008
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
22/2/234    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shrivastav, S.
Right arrow Articles by Kopp, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shrivastav, S.
Right arrow Articles by Kopp, J. B.

Submitted on March 5, 2007
Accepted on October 3, 2007

HIV-1 Vpr suppresses transcriptional activity of PPAR{gamma} and inhibits adipocyte differentiation: Implications for HIV-associated lipodystrophy

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

Kidney Disease Section, National Institute of Diabetes, Digestive and Kidney Diseases, Section on Pediatric Endocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Laboratory of Viral Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA, and Institute of Virology, University of Erlangen, 91054 Erlangen, Germany, Institute of Biochemistry, Humboldt University, 10115, Berlin, Germany, First Department of Pediatrics, University of Athens, 115 27 Athens, Greece

* To whom correspondence should be addressed. E-mail: jbkopp{at}nih.gov.

HIV-1-infected patients may develop lipodystrophy and insulin resistance. We investigated the effect of the HIV-1 accessory protein Vpr on the activity of the peroxisomal proliferator-activating receptor-{gamma} (PPAR{gamma}), a key regulator of adipocyte differentiation and tissue insulin sensitivity. We studied expression of PPAR{gamma} responsive reporter genes in 3T3-L1 mouse adipocytes. We investigated Vpr interaction with the PPAR/RXR-binding site of the c-Cbl associating protein (CAP) gene using the chromatin immunoprecipitation assay, as well as the interaction of Vpr and PPAR{gamma} using co-immunoprecipitation. Finally, we studied the ability of exogenous Vpr protein to enter cultured adipocytes and retard differentiation. We found that Vpr suppressed PPAR{gamma}-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 PPAR{gamma}-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 PPAR{gamma} in an agonist-dependent fashion in vitro. Vpr delivered either by an expression plasmid or as protein added to media suppressed PPAR{gamma} agonist-induced adipocyte differentiation, assessed as lipid accumulation and mRNA expression of the adipocyte differentiation marker aP2 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 PPAR{gamma}-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.
Key words: lipodystrophy • insulin resistance • coactivator • corepressor • 3T3-L1 cells

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ  |  PXR  |  RXRγ
Coregulators:   Vpr  |  p300
Ligands:   Rifampicin  |  GW 9662  |  Dexamethasone  |  Pirinixic acid  |  Mifepristone  |  15-Deoxy-Δ12





HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2007 by The Endocrine Society