Abstract

Although recent data suggest that the nuclear regulatory protein, PPARalpha, interacts with long chain fatty acyl CoA (LCFACoA), it is unclear whether this represents high affinity binding that is physiologically significant. Little is known regarding the distribution of LCFA-CoA to the nucleus or factors that transport LCFA-CoA to the nucleus for regulating nuclear transcription. Liver cytoplasm is rich in high affinity LCFA-CoA binding proteins, fatty acid binding protein (L-FABP) >> acyl CoA binding protein (ACBP). Transcriptional activation of PPARalpha strongly upregulates L-FABP expression. These data led to the hypothesis that LCFA-CoA binding protein(s) regulate the distribution of LCFA-CoA to the nucleus for interaction with and regulation of PPARalpha transcriptional activity.
The specific aims are to:
Aim 1. Determine if PPARalpha binds LCFA-CoA with high affinity, in the physiological range of nuclear LCFA-CoA levels.
Aim 2. Resolve whether L-FABP regulates LCFA-CoA distribution to the nucleus.
Aim 3. Elucidate whether L-FABP directly interacts with PPARalpha in the nucleus.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK066732-03
Application #
7039088
Study Section
Special Emphasis Panel (ZRG1-F06 (20))
Program Officer
Hyde, James F
Project Start
2006-04-01
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$50,428
Indirect Cost

  Institution

Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845

  Publications

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
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
Hostetler, Heather A; Kier, Ann B; Schroeder, Friedhelm (2006) Very-long-chain and branched-chain fatty acyl-CoAs are high affinity ligands for the peroxisome proliferator-activated receptor alpha (PPARalpha). Biochemistry 45:7669-81
Schroeder, Friedhelm; Huang, Huan; Hostetler, Heather A et al. (2005) Stability of fatty acyl-coenzyme A thioester ligands of hepatocyte nuclear factor-4alpha and peroxisome proliferator-activated receptor-alpha. Lipids 40:559-68
Hostetler, Heather A; Petrescu, Anca D; Kier, Ann B et al. (2005) Peroxisome proliferator-activated receptor alpha interacts with high affinity and is conformationally responsive to endogenous ligands. J Biol Chem 280:18667-82