Fatty acid binding proteins, FABPs, have been identified as central regulators of both metabolic and inflammatory pathways. FABPs act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. We have shown that adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol trafficking and inflammatory function, in part via regulation of the activity of the peroxisome proliferator-activated receptor (PPAR-?). Macrophages and dendritic cells (DC) from FABP- deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the promotion of proinflammatory T cells responses during antigen presentation. FABP-deficient mice are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall, the results of our research suggest that FABPs regulate a molecular switch between metabolic and inflammatory pathways in macrophages and DC and, as a consequence, regulate both innate and adaptive immune responses. We will continue our studies of these proteins through the pursuit of the following specific aims:
Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs affect inflammatory cytokine gene expression in macrophages and DC. We have found that FABP-deficiency is accompanied by elevated activity of AMP- activated protein kinase (AMPK) and that AMPK is a negative regulator of macrophage inflammatory function. Experiments will be performed to determine the link between FABPs, AMPK, and PPAR-? testing the hypothesis that FABP regulation of energy stores regulates AMPK activity, which in turn modulates inflammatory activity.
Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using EAE as a model.
This aim will include an evaluation of the specific contributions of T cell priming, and of the tissue environment, towards the protection from EAE displayed by FABP-deficient mice. In this aim we will also test the in vivo efficacy of inhibitors of FABPs as an anti-inflammatory therapy using the EAE model.
Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in leukocyte populations and the association of diet-induced FABP expression with inflammatory responsiveness. The completion of these studies will provide a more comprehensive understanding of how FABPs regulate immune and inflammatory responses.

Public Health Relevance

Fatty acid-binding proteins (FABPs) have been shown to play a role in obesity and Type 2 diabetes. This proposal is based on studies demonstrating that FABPs also strongly promote inflammation and contribute to autoimmune inflammatory disease. The goals of the project are to determine the mechanisms by which FABPs regulate inflammatory function in leukocytes and to test the hypothesis that FABPs constitute an accessible and effective target for treatment of inflammatory disease. Given the recent identification of small molecule inhibitors of FABP function, this project has direct relevance to human health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Peyman, John A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 16 publications