Macrophage-derived apolipoprotein E ameliorates dyslipidemia and atherosclerosis in obese apolipoprotein E-deficient mice
American Journal of Physiology. Endocrinology and Metabolism
Previous studies have demonstrated that macrophage-derived apolipoprotein E (apoE) reduces atherosclerotic lesion formation in lean apoE-deficient ( Ϫ/Ϫ ) mice. apoE has also been demonstrated to play a role in adipocyte differentiation and lipid accumulation. Because the prevalence of obesity has grown to epidemic proportions, we sought to determine whether macrophage-derived apoE could impact atherosclerotic lesion formation or adipose tissue expansion and inflammation in obese apoE Ϫ/Ϫ mice.
... bese apoE Ϫ/Ϫ mice. To this end, we transplanted obese leptin-deficient (ob/ob) apoE Ϫ/Ϫ mice with bone marrow from either ob/ob;apoE Ϫ/Ϫ or ob/ob;apoE ϩ/ϩ donors. There were no differences in body weight, total body adipose tissue, or visceral fat pad mass between recipient groups. The presence of macrophage-apoE had no impact on adipose tissue macrophage content or inflammatory cytokine expression. Recipients of apoE ϩ/ϩ marrow demonstrated 3.7-fold lower plasma cholesterol (P Ͻ 0.001) and 1.7-fold lower plasma triglyceride levels (P Ͻ 0.01) by 12 wk after transplantation even though apoE was present in plasma at concentrations Ͻ10% of wild-type levels. The reduced plasma lipids reflected a dramatic decrease in very low density lipoprotein and a mild increase in high-density lipoprotein levels. Atherosclerotic lesion area was Ͼ10-fold lower in recipients of ob/ob;apoE ϩ/ϩ marrow (P Ͻ 0.005). Similar results were seen in leptin receptor-deficient (db/db) apoE Ϫ/Ϫ mice. Finally, when bone marrow transplantation was performed in 4-mo-old ob/ob;apoE Ϫ/Ϫ and db/db;apoE Ϫ/Ϫ mice with preexisting lesions, recipients of apoE ϩ/ϩ marrow had a 2.8-fold lower lesion area than controls (P ϭ 0.0002). These results demonstrate that macrophage-derived apoE does not impact adipose tissue expansion or inflammatory status; however, even very low levels of macrophage-derived apoE are capable of reducing plasma lipids and atherosclerotic lesion area in obese mice. obesity; very low-density lipoproteins; hyperlipidemia; atherosclerotic lesions OBESITY IS A GROWING worldwide epidemic and is known to increase the risk of atherosclerotic cardiovascular disease (1, 12, 25) . Thus it is imperative that studies on well-known anti-atherogenic targets be conducted in the context of obesity. There are many different obese mouse models available to study metabolic disease; however, most of these models are relatively resistant to high-fat diet-induced atherosclerosis. For example, leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice have elevated high-density lipoprotein (HDL) levels (6, 26, 30, 31) and are therefore resistant to atherosclerotic lesion formation (27). To develop obese models that are susceptible to lesion formation, we have crossed the ob/ob and