Abstract

? The peroxisome proliferator activated-receptor ( (PPAR() plays a central role in energy homeostasis by initiating transcription of multiple genes in fatty acid and glucose metabolism, while concomitantly downregulating genes in insulin signaling. In liver, PPAR( induces transcription of many genes involved in fatty acid degradation by (-oxidation, fatty acid uptake and transport, and lipoprotein metabolism. Thus, PPAR( is responsible for control of a number of lipid metabolic proteins that may contribute to obesity, diabetes, lipotoxicity, and subsequent cardiovascular disorders. However, relatively little is known regarding either the mechanisms that regulate the availability of endogenous fatty acyl-CoA ligands to the nucleus for interaction with PPAR( or the effect of these ligands on PPAR( interaction with heterodimer partners. Although it is known that PPAR( must heterodimerize with either the retinoid X receptor (RXR) or the liver X receptor (LXR) prior to binding DNA response elements, for transcriptional regulation, surprisingly little is known about the effect of endogenous ligands on the choice of heterodimer partners. Furthermore, the effect of PPAR( ligands on heterodimer partners is incompletely resolved. In order to address these issues, this proposal is focused in two phases: First, the 'mentored phase' will: 1. Resolve whether PPAR(-mediated transcription of genes is regulated by long-chain fatty acyl-CoAs (LCFA-CoA). 2. Determine the effect of LCFA-CoA on the molecular interaction of PPAR( with L-FABP. Second, the 'independent phase' will: 3. Determine if LXR( binds LCFA-CoA with high affinity, in the physiological range of nuclear LCFA-CoA levels. 4. Elucidate the effect of LCFA-CoA on the molecular interaction of PPAR( with LXR(. It is hoped that the results of this work will provide a mechanistic role of LCFA-CoAs in nuclear receptor regulation. ? Relevance to Public Health: This work aims at studying a protein whose abnormal expression/regulation is associated with obesity, diabetes, and cardiovascular disease. This research is a step towards the development of new methods and more efficient drugs for the treatment of such disorders. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
5K99DK077573-02
Application #
7324820
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Laughlin, Maren R
Project Start
2007-04-01
Project End
2009-09-24
Budget Start
2008-04-01
Budget End
2009-09-24
Support Year
2
Fiscal Year
2008
Total Cost
$89,662
Indirect Cost

  Institution

Name
Texas Agrilife Research
Department
Physiology
Type
Schools of Earth Sciences/Natur
DUNS #
847205713
City
College Station
State
TX
Country
United States
Zip Code
77843

  Publications

Bedi, Shimpi; Hines, Genesis Victoria; Lozada-Fernandez, Valery V et al. (2017) Fatty acid binding profile of the liver X receptor ?. J Lipid Res 58:393-402
Mahankali, Madhu; Farkaly, Terry; Bedi, Shimpi et al. (2015) Phosphatidic Acid (PA) can Displace PPAR?/LXR? Binding to The EGFR Promoter Causing its Transrepression in Luminal Cancer Cells. Sci Rep 5:15379
Balanarasimha, Madhumitha; Davis, Andrea M; Soman, Frances L et al. (2014) Ligand-regulated heterodimerization of peroxisome proliferator-activated receptor ? with liver X receptor ?. Biochemistry 53:2632-43
Oswal, Dhawal P; Balanarasimha, Madhumitha; Loyer, Jeannette K et al. (2013) Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities. J Lipid Res 54:2354-65
McIntosh, Avery L; Petrescu, Anca D; Hostetler, Heather A et al. (2013) Liver-type fatty acid binding protein interacts with hepatocyte nuclear factor 4?. FEBS Lett 587:3787-91
Kiselyuk, Alice; Lee, Seung-Hee; Farber-Katz, Suzette et al. (2012) HNF4? antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chem Biol 19:806-18
Hostetler, Heather A; Balanarasimha, Madhumitha; Huang, Huan et al. (2010) Glucose regulates fatty acid binding protein interaction with lipids and peroxisome proliferator-activated receptor ?. J Lipid Res 51:3103-16
Hostetler, Heather A; McIntosh, Avery L; Atshaves, Barbara P et al. (2009) L-FABP directly interacts with PPARalpha in cultured primary hepatocytes. J Lipid Res 50:1663-75
McIntosh, Avery L; Atshaves, Barbara P; Hostetler, Heather A et al. (2009) Liver type fatty acid binding protein (L-FABP) gene ablation reduces nuclear ligand distribution and peroxisome proliferator-activated receptor-alpha activity in cultured primary hepatocytes. Arch Biochem Biophys 485:160-73
Hostetler, Heather A; Huang, Huan; Kier, Ann B et al. (2008) Glucose directly links to lipid metabolism through high affinity interaction with peroxisome proliferator-activated receptor alpha. J Biol Chem 283:2246-54

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