Published online before print October 15, 2009, doi: 10.1161/CIRCRESAHA.109.199570
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Submitted on April 20, 2009
Revised on September 28, 2009
Accepted on October 2, 2009
Defective Phagocytosis of Apoptotic Cells by Macrophages in Atherosclerotic Lesions of ob/ob Mice and Reversal by a Fish Oil Diet
Suzhao Li *;
From the Departments of Medicine (S.L., Y.S., C.-P.L., E.B.T., S.H., A.W.J., R.L., C.L.W., I.T., A.R.T.), Physiology & Cellular Biophysics (S.L., I.T., A.R.T.), and Pathology & Cell Biology (I.T.), Columbia University, New York; Department of Molecular Physiology and Biophysics (V.S., A.H.H.), Vanderbilt University, Nashville, Tenn; Laboratory of Biochemical Genetics and Metabolism (B.P., J.L.B.), Rockefeller University, NY; Department of Pathology (J.E.K., K.E.B.), Diabetes and Obesity Center of Excellence, University of Washington, Seattle.
* To whom correspondence should be addressed. E-mail: sl2181{at}columbia.edu.
Rationale: The complications of atherosclerosis are a major cause of death and disability in type 2 diabetes. Defective clearance of apoptotic cells by macrophages (efferocytosis) is thought to lead to increased necrotic core formation and inflammation in atherosclerotic lesions.
Objective: To determine whether there is defective efferocytosis in a mouse model of obesity and atherosclerosis.
Methods and Results: We quantified efferocytosis in peritoneal macrophages and in atherosclerotic lesions of obese ob/ob or ob/ob;Ldlr-/- mice and littermate controls. Peritoneal macrophages from ob/ob and ob/ob;Ldlr-/- mice showed impaired efferocytosis, reflecting defective phosphatidylinositol 3-kinase activation during uptake of apoptotic cells. Membrane lipid composition of ob/ob and ob/ob;Ldlr-/- macrophages showed an increased content of saturated fatty acids (FAs) and decreased 
-3 FAs (eicosapentaenoic acid and docosahexaenoic acid) compared to controls. A similar defect in efferocytosis was induced by treating control macrophages with saturated free FA/BSA complexes, whereas the defect in ob/ob macrophages was reversed by treatment with eicosapentaenoic acid/BSA or by feeding ob/ob mice a fish oil diet rich in -3 FAs. There was also defective macrophage efferocytosis in atherosclerotic lesions of ob/ob;Ldlr-/- mice and this was reversed by a fish oil–rich diet.
Conclusions: The findings suggest that in obesity and type 2 diabetes elevated levels of saturated FAs and/or decreased levels of -3 FAs contribute to decreased macrophage efferocytosis. Beneficial effects of fish oil diets in atherosclerotic cardiovascular disease may involve improvements in macrophage function related to reversal of defective efferocytosis and could be particularly important in type 2 diabetes and obesity.
Key words: efferocytosis • macrophages • atherosclerosis • fatty acids • mouse