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Dissertation
Investigating the role of nuclear receptors in HIV/HAART-associated dyslipidemic lipodystrophy
Doctor of Philosophy (Ph.D.), Drexel University
May 2007
DOI:
https://doi.org/10.17918/etd-1759
Abstract
The use of highly active antiretroviral therapy (HAART) to manage HIV infection is associated with the development of HIV/HAART-associated dyslipidemic lipodystrophy (HADL). HADL symptoms are comprised of metabolic dysfunctions resulting in hyperlipidemia, fat redistribution, and insulin resistance. The direct interaction of HIV drugs with nuclear receptors involved in metabolic pathways has been largely unexplored. HIV drugs were evaluated for effect on the activation of farsenoid X receptor (FXR), liver X receptor alpha (LXR[alpha]), retinoid X receptor alpha (RXR[alpha]), pregnane X receptor (PXR) and the peroxisome proliferator-activated receptor family (PPAR [alpha], [gamma], and [delta]). Our results indicate direct inhibition of PPAR[alpha] and PPAR[gamma] activation by protease inhibitors (PIs) in both coactivator recruitment and reporter gene assays. Gene chip analysis demonstrated that saquinavir and ritonavir reduced the expression level of PPAR[gamma] target genes in primary human hepatocytes. Partial recovery of mRNA levels of glucokinase (GK) and GLUT2 was achieved when hepatocytes were incubated in combination with the PPAR[gamma] agonist troglitazone. Decreased glucose sensing capabilities through PI-mediated inhibition of PPAR[gamma] activation may be a contributing factor in symptoms of HADL. PPAR[alpha] is the nuclear receptor responsible for regulating genes that control lipid homeostasis. Because of this role, PPAR[alpha] has become a target of interest for the development of drugs to treat diseases such as dyslipidemia, obesity and atherosclerosis. Assays currently employed to determine potency and efficacy of potential drug candidates typically utilize a truncated form of the native receptor, one which lacks the entire N-terminal region of the protein. We report that differences in PPAR[alpha] full length and ligand binding domain constructs result in differences in binding affinity for coactivator peptides, but have little effect on potency of agonists in both cell free and cell based nuclear receptor assays.
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Details
- Title
- Investigating the role of nuclear receptors in HIV/HAART-associated dyslipidemic lipodystrophy
- Creators
- Jennifer Berbaum - DU
- Contributors
- Joseph Edward Bentz (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Bioscience and Biotechnology [Historical]; College of Arts and Sciences; Drexel University
- Other Identifier
- 1759; 991014632697404721