Insulin resistance is a condition associated with a cluster of abnormalities including hypertension, glucose intolerance, hypertriglyceridemia, obesity and premature coronary artery disease. Understanding the molecular basis of the link between insulin resistance and these pathological states has been a difficult task. Elevated plasma levels of free fatty acids are a common hallmark of insulin resistance. Cytoplasmic fatty acid binding proteins (FABP) are small cytoplasmic proteins that bind a variety of fatty acids and are expressed in a tightly regulated, tissue specific manner. Proposed functions of cytoplasmic FABP include trapping and trafficking of fatty acids within cells and cell signaling. Targeted disruption of the aP2 allele has been shown to uncouple obesity and insulin resistance, indicating an important role for aP2 in the insulin resistance. Preliminary studies indicate that aP2 promotes atherosclerosis and macrophage foam cell formation in apoE deficient mice. Mall, a closely related FABP, is also expressed by adipocytes and macrophages and is up-regulated in aP2 deficient mice. The goal of this project is to investigate the impact of aP2 and mall-deficiency on insulin resistance and atherosclerosis. To this end, murine bone marrow transplantation will be used to generate mice chimeric for aP2 and or mall expression by macrophages and or adipocytes allowing the investigation of the relative cell-specific contributions of expression of these genes to atherosclerosis and insulin resistance. Finally, in vitro studies will investigate the role of aP2 and mall in macrophage foam cell formation. By providing new insights into the link between insulin resistance and atherosclerosis, these studies may lead to new therapeutic approaches to diabetes and coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065405-04
Application #
6637296
Study Section
Pathology A Study Section (PTHA)
Program Officer
Ershow, Abby
Project Start
2000-08-01
Project End
2004-12-31
Budget Start
2003-08-01
Budget End
2004-12-31
Support Year
4
Fiscal Year
2003
Total Cost
$419,948
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
Woo, Kel Vin; Qu, Xianghu; Babaev, Vladimir R et al. (2011) Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress-specific manner. J Clin Invest 121:1624-35
Babaev, Vladimir R; Runner, Robert P; Fan, Daping et al. (2011) Macrophage Mal1 deficiency suppresses atherosclerosis in low-density lipoprotein receptor-null mice by activating peroxisome proliferator-activated receptor-?-regulated genes. Arterioscler Thromb Vasc Biol 31:1283-90
Babaev, Vladimir R; Whitesell, Richard R; Li, Liying et al. (2011) Selective macrophage ascorbate deficiency suppresses early atherosclerosis. Free Radic Biol Med 50:27-36
Babaev, Vladimir R; Li, Liying; Shah, Sanket et al. (2010) Combined vitamin C and vitamin E deficiency worsens early atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 30:1751-7
Linton, Macrae F; Fazio, Sergio (2010) 6-Mercaptopurine, monocytes, and atherosclerosis. Arterioscler Thromb Vasc Biol 30:1494-6
Yancey, Patricia G; Blakemore, John; Ding, Lei et al. (2010) Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler Thromb Vasc Biol 30:787-95
Zuo, Yiqin; Yancey, Patricia; Castro, Iris et al. (2009) Renal dysfunction potentiates foam cell formation by repressing ABCA1. Arterioscler Thromb Vasc Biol 29:1277-82
Erbay, Ebru; Babaev, Vladimir R; Mayers, Jared R et al. (2009) Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med 15:1383-91
Fazio, Sergio; Linton, MacRae F (2009) Elevated high-density lipoprotein (HDL) levels due to hepatic lipase mutations do not reduce cardiovascular disease risk: another strike against the HDL dogma. J Clin Endocrinol Metab 94:1081-3
Su, Yan Ru; Blakemore, John L; Zhang, Youmin et al. (2008) Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis. Arterioscler Thromb Vasc Biol 28:1439-46

Showing the most recent 10 out of 49 publications