HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity

Shashi Shrivastav, Liyan Zhang, Koji Okamoto, Hewang Lee, Claudia Lagranha, Yoshifusa Abe, Ashok Balasubramanyam, Gary D. Lopaschuk, Tomoshige Kino, Jeffrey B. Kopp

Research output: Contribution to journalArticle

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Abstract

HIV infection and its therapy are associated with disorders of lipid metabolism and bioenergetics. Previous work has suggested that viral protein R (Vpr) may contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients. In adipocytes, Vpr suppresses mRNA expression of peroxisomal proliferator-activating receptor-γ (PPARγ)-responsive genes and inhibits differentiation. We investigated whether Vpr might interact with PPARβ/δ and influence its transcriptional activity. In the presence of PPARβ/δ, Vpr induced a 3.3-fold increase in PPAR response element-driven transcriptional activity, a 1.9-fold increase in pyruvate dehydrogenase kinase 4 (PDK4) protein expression, and a 1.6-fold increase in the phosphorylated pyruvate dehydrogenase subunit E1α leading to a 47% decrease in the activity of the pyruvate dehydrogenase complex in HepG2 cells. PPARβ/δ knockdown attenuated Vpr-induced enhancement of endogenous PPARβ/δ-responsive PDK4 mRNA expression. Vpr induced a 1.3-fold increase in mRNA expression of both carnitine palmitoyltransferase I (CPT1) and acetyl-coenzyme A acyltransferase 2 (ACAA2) and doubled the activity of β-hydroxylacyl coenzyme A dehydrogenase (HADH). Vpr physically interacted with the ligand-binding domain of PPARβ/δ in vitro and in vivo. Consistent with a role in energy expenditure, Vpr increased state-3 respiration in isolated mitochondria (1.16-fold) and basal oxygen consumption rate in intact HepG2 cells (1.2-fold) in an etomoxirsensitive manner, indicating that the oxygen consumption rate increase is β-oxidation-dependent. The effects of Vpr on PPAR response element activation, pyruvate dehydrogenase complex activity, and β-oxidation were reversed by specific PPARβ/δ antagonists. These results support the hypothesis that Vpr contributes to impaired energy metabolism and increased energy expenditure in HIV patients.

Original languageEnglish
Pages (from-to)1564-1576
Number of pages13
JournalMolecular Endocrinology
Volume27
Issue number9
DOIs
Publication statusPublished - 1 Sep 2013
Externally publishedYes

Fingerprint

Human Immunodeficiency Virus vpr Gene Products
vpr Gene Products
HIV-1
Energy Metabolism
Pyruvate Dehydrogenase Complex
Hep G2 Cells
Response Elements
Oxygen Consumption
Messenger RNA
Pyruvate Dehydrogenase (Lipoamide)
Acetyl-CoA C-Acyltransferase
Lipid Metabolism Disorders
pyruvate dehydrogenase kinase 4
Carnitine O-Palmitoyltransferase
Lipodystrophy
Coenzyme A
Adipocytes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Shrivastav, S., Zhang, L., Okamoto, K., Lee, H., Lagranha, C., Abe, Y., ... Kopp, J. B. (2013). HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity. Molecular Endocrinology, 27(9), 1564-1576. https://doi.org/10.1210/me.2012-1370

HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity. / Shrivastav, Shashi; Zhang, Liyan; Okamoto, Koji; Lee, Hewang; Lagranha, Claudia; Abe, Yoshifusa; Balasubramanyam, Ashok; Lopaschuk, Gary D.; Kino, Tomoshige; Kopp, Jeffrey B.

In: Molecular Endocrinology, Vol. 27, No. 9, 01.09.2013, p. 1564-1576.

Research output: Contribution to journalArticle

Shrivastav, S, Zhang, L, Okamoto, K, Lee, H, Lagranha, C, Abe, Y, Balasubramanyam, A, Lopaschuk, GD, Kino, T & Kopp, JB 2013, 'HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity', Molecular Endocrinology, vol. 27, no. 9, pp. 1564-1576. https://doi.org/10.1210/me.2012-1370
Shrivastav, Shashi ; Zhang, Liyan ; Okamoto, Koji ; Lee, Hewang ; Lagranha, Claudia ; Abe, Yoshifusa ; Balasubramanyam, Ashok ; Lopaschuk, Gary D. ; Kino, Tomoshige ; Kopp, Jeffrey B. / HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 9. pp. 1564-1576.
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