Combined adipocyte-macrophage fatty acid-binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice

Abstract

Background: The adipocyte fatty acid-binding protein (FABP) aP2 is expressed by adipocytes and macrophages and modulates insulin resistance, glucose and lipid metabolism, and atherosclerosis. Insulin sensitivity is improved in obese but not in lean aP2-deficient mice. A second fatty acid-binding protein, mal1, also is expressed in adipocytes and macrophages, and mal1 deficiency produces similar effects on insulin resistance. We tested the hypothesis that combined aP2 and mal1 deficiency would produce synergistic effects on metabolism and reduce atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice.

Methods and results: Male and female apoE-/- mice null for both aP2 and mal1 (3KO) and apoE-/- controls were fed a low-fat chow diet for 16 or 56 weeks. Lean 3KO mice had significantly lower serum cholesterol and triglycerides as well as improved insulin and glucose tolerance as compared with controls. Analysis of atherosclerotic lesions in the 3KO mice showed dramatic reductions in both early (20 weeks) and late-stage (60 weeks) atherosclerosis. Strikingly, survival in the 3KO mice was improved by 67% as compared with apoE-/- controls when challenged with the Western diet for 1 year.

Conclusions: Combined aP2 and mal1 deficiency improved glucose and lipid metabolism, reduced atherosclerosis, and improved survival in apoE-/- mice, making these proteins important therapeutic targets for the prevention of the cardiovascular consequences of the metabolic syndrome.

Figure 1

Lipoprotein distribution by FPLC for 3KO and apoE^−/− mice. Samples drawn from male (A) and female (B) mice at 20 weeks of age after 12-h fast. Data are average distribution of total cholesterol per fraction in mg/dL for each group. Fractions 14 to 18 contain VLDL; fractions 19 to 25, IDL/LDL; and fractions 26 to 31, HDL. Fractions 32 to 40 contain non–lipoprotein-associated proteins.

Figure 2

GTT and ITT in 3KO and apoE^−/− mice. ITT (0.5 U/kg, IP) shown for male (A) and female (B) mice. GTT (1.8 g/kg, IP) shown for male (C) and female (D) mice. Each data point represents mean glucose level (mg/dL)±SEM *P<0.05, as compared with control group.

Figure 3

Immunocytochemical detection of macrophages and mal1 expression in atherosclerotic lesions. Proximal aorta atherosclerotic lesions in aP2^−/− apoE^−/− and aP2^−/− mal1^−/− apoE^−/− mice stained with MOMA-2 to detect macrophages (A, B); mal1 expression (C, D) shown with rabbit antiserum against human mal1 (magnification ×400).

Figure 4

Atherosclerosis in proximal and en face aorta in 3KO and apoE^−/− mice. Atherosclerosis in 20-week-old male and female mice in proximal aorta (A) and en face aorta (B). Quantification of atherosclerosis for male 60-week-old mice in proximal aorta (C) and en face aorta (D). Data shown as mean lesion area ±SEM for each group. *P<0.05. E, representative pinned-out en face aorta preparations from male 60-week-old mice stained with Sudan-IV, exemplifying dramatic reduction in lesion area in 3KO mice as compared with apoE^−/− controls (magnification ×20).

Figure 5

Survival curve for 3KO and apoE^−/− mice on high-fat diet. Male 3KO and apoE^−/− mice fed high-fat Western diet at 1 month of age for 1 y. 3KO mice show significantly increased survival at 12 months of age.