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

Mol Endocrinol. 2013 Sep;27(9):1564-76. doi: 10.1210/me.2012-1370. Epub 2013 Jul 10.

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 etomoxir-sensitive 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases
  • Gene Expression Regulation, Neoplastic / drug effects
  • HIV-1 / metabolism*
  • Hep G2 Cells
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • Mutant Proteins / metabolism
  • Oxygen Consumption / drug effects
  • PPAR delta / agonists
  • PPAR delta / metabolism*
  • PPAR-beta / agonists
  • PPAR-beta / metabolism*
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Kinases / metabolism*
  • Pyruvate Dehydrogenase Complex / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Thiazoles / pharmacology
  • Transcription, Genetic*
  • Transfection
  • vpr Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • GW 501516
  • Mutant Proteins
  • PPAR delta
  • PPAR-beta
  • Pyruvate Dehydrogenase Complex
  • RNA, Messenger
  • Thiazoles
  • vpr Gene Products, Human Immunodeficiency Virus
  • 3-Hydroxyacyl CoA Dehydrogenases
  • Protein Kinases
  • pyruvate dehydrogenase kinase 4