The fatty acid binding proteins (FABP) aP2 and mal1, which are expressed in both adipocytes and macrophages, influence insulin sensitivity and atherogenesis. Deficiency of aP2 or mal1 results in improvements in insulin sensitivity in obese mice but not in lean mice. In contrast, apoE deficient mice lacking both aP2 and mal1 show improved insulin sensitivity even in the lean state. Macrophage-specific deletion of aP2 reduces plaque growth in apoE deficient mice, independent of effects on insulin sensitivity. aP2 deficiency impacts both the inflammatory response and cholesterol homeostasis in macrophages. In contrast mal1 deficiency does not reduce atherosclerosis in apoE deficient mice, suggesting that these FABP have different functions in the macrophage. Yet, mice harboring the combined deficiency of aP2 and nail have less insulin resistance, less atherogenesis, and an increased survival rate compared to controls. First, we propose evaluating the hypothesis that macrophage and adipocyte aP2 expression both promote atherosclerosis, using bone marrow transplantation studies.
In Specific Aim 2, we propose comparing the relative impact of macrophage deficiency of aP2, mall or both on atherogenesis in the absence of insulin resistance.
In Specific Aim 3, the molecular mechanisms by which aP2 and mall affect macrophage lipid homeostasis will be examined, and aP2 trafficking and protein-protein interactions in macrophages will be studied in Specific Aim 4. Mice deficient in c-Jun N-terminal protein kinase (JNK1), a signal transduction protein capable of modulating inflammatory pathways, are protected from diet-induced insulin resistance and obesity. There are obvious parallels between the JNK1 deficient and FABP deficient mice. Therefore, we plan to study the impact of JNK1 deficiency on atherosclerosis. Hence, FABP constitute a major opportunity to understand the mechanisms underlying atherosclerosis, the metabolic syndrome, and type 2 diabetes. These studies may lead to new theraputic approaches to atherogenesis and the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065405-09
Application #
7572886
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2000-08-01
Project End
2009-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
9
Fiscal Year
2009
Total Cost
$466,721
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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