title: HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity.
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.
authors.affiliation: Kidney Disease Section, National Institute of Diabetes and Digestive andKidney Diseases, National Institutes of Health,Bethesda, Maryland 20892-1268, USA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Shrivastav
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hewang
authors.initials: H
authors.lastname: Lee
authors.forename: Claudia
authors.initials: C
authors.lastname: Lagranha
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Abe
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015497:HIV-1 / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C425931:GW 501516; D050505:Mutant Proteins; D047494:PPAR delta; D048068:PPAR-beta; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D013844:Thiazoles; D054325:vpr Gene Products, Human Immunodeficiency Virus; D015094:3-Hydroxyacyl CoA Dehydrogenases; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4