MOLECULAR BASIS OF HIV LIPODYSTROPHY: ROLE OF VPR

Summary

Principal Investigator: Ashok Balasubramanyam
Abstract: DESCRIPTION (Adapted from the applicant's abstract) The unified objective of the 2 R01 projects in this RFA is to specify a key molecular mechanisms underlying HIV-associated lipodystrophy syndrome (HLS), and the consequent metabolic derangements that lead to its clinical manifestations. These manifestations suggest increased glucocorticoid sensitivity in fat, muscle and liver. Recent work shows that an HIV-1 viral protein, Vpr, potentiates ligand-mediated activation of the glucocorticoid receptor (GR), and antagonized PPAR-gamma mediated gene transcription. Preliminary studies also show that HLS patients have lipid and glucose kinetics consistent with these molecular effects of Vpr. The hypotheses for the Basic Science R01 project are that a) over expression of Vpr in mice leads to metabolic changes characteristic of GR activation; b) Vpr affects adipogenesis and lipogenesis differentially in central vs. peripheral adipocytes; c) Vpr exerts these effects by direct interactionwith the transcriptional complexes of the GR and PPAR-gamma, leading to activation of GR-regulated genes and inhibition of PPAR-gamma regulated genes. The Specific Aims are: a) measurements of body composition and lipid, protein and glucose metabolism, using stable isotopes/mass spectrometry, in transgenic mice over expressing Vpr, following dietary manipulations and protease inhibitor administration; b) functional assays of adipogenesis and lipogenesis in central vs. peripheral adipocytes removed from these mice; c) molecular dissection of the mechanism and effects of Vpr-mediated regulation of the GR and PPAR-gamma in preadipocyte cell lines and primary cultures of human preadipocytes derived from abdominal and peripheral fat depots. The hypotheses for the clinical Science R01 are that a) patients who develop HLS progressively manifest the metabolic effects of persistent GR activation fat, muscle, and liver, namely, increased whole body lipolysis, increased hepatic lipogenesis, enhanced triglyceride storage in abdominal fat, increased protein turnover, and elevated endogenous glucose production while fasting and feeding; b) these changes are secondary to increased sensitivity to glucocorticoids due to the actions of Vpr. The Specific Aims involve longitudinal, intensive GCRC studies on newly diagnosed HIV-infected patients and matched normal subjects, to measure; a) whole body lipid kinetics (lipolysis, lipogenesis, reesterification, VLDL synthesis, triglyceride utilization), regional lipolysis, protein turnover, and endogenous glucose production, while feeding and fasting, using stable isotopes/mass spectrometry b) glucocorticoid sensitivity towards proteolysis and lipolysis; c) Vpr concentrations in plasma, abdominal fat- and thigh fat-extracellular fluid; d) detailed body composition and biochemical parameters of HLS. These projects will be performed by a coordinated team experienced in metabolic protocols and stable isotope techniques, HIV clinical specialists, and experts in the molecular biology of the GR and Vpr. They will detail a molecular pathway to this novel lipodystrophic syndrome, which likely predates the use of effective anti-retroviral therapy but comes clinically obvious during therapy as a result of increased nutrient intake, and translate to clinical science the Vpr-mediated mechanism of metabolic dysregulation.
Funding Period: 2001-08-01 - 2005-06-30
more information: NIH RePORT

Top Publications

  1. pmc Serum response factor MADS box serine-162 phosphorylation switches proliferation and myogenic gene programs
    Dinakar Iyer
    Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 103:4516-21. 2006
  2. ncbi Influenza A virus protein PB1-F2: synthesis and characterization of the biologically active full length protein and related peptides
    Peter Henklein
    Humboldt University, Institute of Biochemistry, Berlin, Germany
    J Pept Sci 11:481-90. 2005
  3. ncbi Severely dysregulated disposal of postprandial triacylglycerols exacerbates hypertriacylglycerolemia in HIV lipodystrophy syndrome
    Rajagopal V Sekhar
    Translation Metabolism Unit, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030 2600, USA
    Am J Clin Nutr 81:1405-10. 2005
  4. ncbi Regulation of body weight by proopiomelanocortin peptides in humans: lessons from the Nelson syndrome
    Rajagopal V Sekhar
    Ann Intern Med 143:238-9. 2005
  5. ncbi Physiologic growth hormone replacement improves fasting lipid kinetics in patients with HIV lipodystrophy syndrome
    Susana D'Amico
    Translational Metabolism Unit and the Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030 2600, USA
    Am J Clin Nutr 84:204-11. 2006
  6. ncbi Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice
    Ashok Balasubramanyam
    Translational Metabolism Unit, Division of Diabetes, Endocrinology and Metabolism, BCM 700B, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Am J Physiol Endocrinol Metab 292:E40-8. 2007
  7. pmc Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy
    Shashi Shrivastav
    Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease NIH, 10 Center Drive MSC 1268, Bethesda, MD 20892 1268, USA
    Mol Endocrinol 22:234-47. 2008

Scientific Experts

  • Ashok Balasubramanyam
  • Peter Henklein
  • Rajagopal V Sekhar
  • Dinakar Iyer
  • Shashi Shrivastav
  • Susana D'Amico
  • Khaleel Rehman
  • Farook Jahoor
  • George P Chrousos
  • Ulrich Schubert
  • Tshaka Cunningham
  • Tomoshige Kino
  • Takamasa Ichijo
  • Peter Heinklein
  • Jeffrey B Kopp
  • Eric N Olson
  • Joe Marx
  • Mario Maldonado
  • James Willis
  • David Chang
  • Kenneth J Ellis
  • Lei Wei
  • Michael S Parmacek
  • Robert J Schwartz
  • Jianjian Shi
  • J Clay Goodman
  • Jeffrey B Tatro
  • Emese Mihaly
  • Henry J Pownall
  • John Gaubatz

Detail Information

Publications7

  1. pmc Serum response factor MADS box serine-162 phosphorylation switches proliferation and myogenic gene programs
    Dinakar Iyer
    Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 103:4516-21. 2006
    ..Hence, the phosphorylation status of serine-162 in the alphaI coil may constitute a novel switch that directs target gene expression into proliferation or differentiation programs...
  2. ncbi Influenza A virus protein PB1-F2: synthesis and characterization of the biologically active full length protein and related peptides
    Peter Henklein
    Humboldt University, Institute of Biochemistry, Berlin, Germany
    J Pept Sci 11:481-90. 2005
    ....
  3. ncbi Severely dysregulated disposal of postprandial triacylglycerols exacerbates hypertriacylglycerolemia in HIV lipodystrophy syndrome
    Rajagopal V Sekhar
    Translation Metabolism Unit, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030 2600, USA
    Am J Clin Nutr 81:1405-10. 2005
    ..One mechanism is accelerated lipolysis in the fasted state, but the severity of the hypertriacylglycerolemia suggests that additional underlying abnormalities may exist in the disposal of dietary fat...
  4. ncbi Regulation of body weight by proopiomelanocortin peptides in humans: lessons from the Nelson syndrome
    Rajagopal V Sekhar
    Ann Intern Med 143:238-9. 2005
  5. ncbi Physiologic growth hormone replacement improves fasting lipid kinetics in patients with HIV lipodystrophy syndrome
    Susana D'Amico
    Translational Metabolism Unit and the Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030 2600, USA
    Am J Clin Nutr 84:204-11. 2006
    ..The effect of growth hormone (GH) replacement on these lipid kinetic abnormalities is unknown...
  6. ncbi Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice
    Ashok Balasubramanyam
    Translational Metabolism Unit, Division of Diabetes, Endocrinology and Metabolism, BCM 700B, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Am J Physiol Endocrinol Metab 292:E40-8. 2007
    ....
  7. pmc Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy
    Shashi Shrivastav
    Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease NIH, 10 Center Drive MSC 1268, Bethesda, MD 20892 1268, USA
    Mol Endocrinol 22:234-47. 2008
    ..Vpr may alter sensitivity to insulin and thereby contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients...