Adipocyte fatty acid-binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolemia

Abstract

Objective: The adipocyte fatty acid-binding protein, aP2, has important effects on insulin resistance, lipid metabolism, and atherosclerosis. Its expression in macrophages enhances early foam cell formation and atherosclerosis in vivo. This study was designed to determine whether aP2 deficiency has a similar effect in the setting of advanced atherosclerosis and severe hypercholesterolemia.

Methods and results: Mice deficient in aP2 and apolipoprotein E (aP2(-/-)apoE(-/-) mice) and apolipoprotein E-deficient control mice (apoE(-/-) mice) were fed a Western diet for 14 weeks. No significant differences in fasting serum levels of cholesterol, triglycerides, or free fatty acids were found between groups for each sex. Compared with apoE(-/-) control mice, male and female aP2(-/-)apoE(-/-) mice had significant reductions in mean atherosclerotic lesion size in the proximal aorta, en face aorta, and innominate/right carotid artery. Feeding the Western diet in the apoE-deficient background did not cause a significant reduction in insulin sensitivity in vivo, as determined by steady-state serum glucose levels and insulin tolerance testing.

Conclusions: These data demonstrate an important role for aP2 expression in the advanced stages of atherosclerotic lesion formation. Thus, aP2 provides an important physiological link between different features of the metabolic syndrome and is a potential target for therapy of atherosclerosis.

Figure 1

Lipoprotein distribution in male and female aP2^−/−apoE^−/− and aP2^+/+apoE^−/− mice. Data are an average (n=4 for each group) percent distribution of total cholesterol for each group. Fractions 14 to 17 contain VLDL; fractions 18 to 24, IDL/LDL; and fractions 25 to 29, HDL. Fractions 30 to 40 are non-lipoprotein-associated proteins.

Figure 2

Insulin tolerance tests in male (A) and female (B) aP2^−/−apoE^−/− and aP2^+/+apoE^−/− mice. Insulin tolerance tests were performed with 0.5 U/kg human insulin injected intraperitoneally per animal. Data are mean±SEM. P=NS between groups for all time points in both panels.

Figure 3

Quantification of atherosclerotic lesion area in the proximal aorta (A), en face aorta (B), and innominate/right carotid artery (C) in male and female aP2^−/−apoE^−/− and aP2^+/+apoE^−/− mice. Data are average mean lesion area for each group, with error bars indicating SEM. Probability values are as indicated. Student t test was used for data in panels A and B, and the Mann-Whitney test was used for data in panel C.

Figure 4

Immunocytochemical detection of macrophages in the proximal aorta of male and female aP2^−/−apoE^−/− and aP2^+/+apoE^−/− mice. Macrophages are stained with antibody to mouse macrophage clone, MOMA-2.

Figure 5

Histological appearance of atherosclerotic lesions in the proximal aorta. Each micrograph is a representative section from each group. Frozen 5-μm sections were fixed and stained with Masson's trichrome and captured with an Olympus PRO-VIS AX70 microscope and digital camera at ×200 magnification.