Abstract

Fatty acid binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic ligands and are believed to play a role in lipid transport, enabling delivery of hydrophobic compounds to enzyme systems responsible for metabolism and intracellular signaling. The importance of FABPs has been underscored by recent studies in which genetically engineered mice deficient in expression of adipocyte fatty acid binding protein (aP2) were found to display profound protection from both obesity-induced diabetes and atherosclerosis. Macrophages express high levels of aP2 and keratinocyte fatty acid binding protein (mal-1). AP2 and mal-1 are FABPs which have been demonstrated to bind several identified ligands for the peroxisome proliferator-activated receptors (PPARs) which include metabolites of cyclooxygenase and lipoxygenase. PPAR family members have been demonstrated to play an important role in the regulation of gene expression in macrophages. This proposal tests the hypothesis that FABPs control the availability of PPAR ligands, thus impacting macrophage gene expression and function. Experiments have been designed which distinguish between a role of FABPs in sequestration of PPAR ligands versus the synthesis of PPAR ligands. PPAR activity will be assessed, and the activity of transcription factors known to be regulated by PPARs will be analyzed in wild-type and FABP-deficient macrophages. Data collected thus far indicate that FABPs act as positive regulators of pro-inflammatory activity, suggesting that absence of FABPs may be protective in autoimmune inflammatory disease. This concept is supported by preliminary data using the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis. This model will be employed to provide a means to analyze FABP function, in vivo, in an autoimmune inflammatory response in which macrophage pro-inflammatory activity has been shown to be key to the progression of disease. These studies may reveal a unique means of modulating macrophage function for therapeutic purposes. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048850-02
Application #
6717641
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Johnson, David R
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$343,159
Indirect Cost

  Institution

Name
University of Louisville
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292

  Publications

Hao, Jiaqing; Yan, Fei; Zhang, Yuwen et al. (2018) Expression of Adipocyte/Macrophage Fatty Acid-Binding Protein in Tumor-Associated Macrophages Promotes Breast Cancer Progression. Cancer Res 78:2343-2355
Rao, Enyu; Zhang, Yuwen; Li, Qiang et al. (2016) AMPK-dependent and independent effects of AICAR and compound C on T-cell responses. Oncotarget 7:33783-95
Rao, Enyu; Singh, Puja; Li, Yan et al. (2015) Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis. BMC Immunol 16:28
Rao, Enyu; Zhang, Yuwen; Zhu, Ganqian et al. (2015) Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death. Oncotarget 6:7944-58
Zhu, Yanfang Peipei; Brown, Jonathan R; Sag, Duygu et al. (2015) Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages. J Immunol 194:584-94
Carroll, Kelly Casey; Viollet, Benoit; Suttles, Jill (2013) AMPK?1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling. J Leukoc Biol 94:1113-21
Vladykovskaya, Elena; Ozhegov, Evgeny; Hoetker, J David et al. (2011) Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids. J Lipid Res 52:2209-25
Ghare, Smita; Patil, Madhuvanti; Hote, Prachi et al. (2011) Ethanol inhibits lipid raft-mediated TCR signaling and IL-2 expression: potential mechanism of alcohol-induced immune suppression. Alcohol Clin Exp Res 35:1435-44
Hertzel, Ann V; Hellberg, Kristina; Reynolds, Joseph M et al. (2009) Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins. J Med Chem 52:6024-31
Stout, Robert D; Watkins, Stephanie K; Suttles, Jill (2009) Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol 86:1105-9

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