Deficiency of CCAAT/Enhancer Binding Protein-Epsilon Reduces Atherosclerotic Lesions in LDLR−/− Mice

<div><p>The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. C/EBPε is expressed only in myeloid cells including monocytes/macrophages. Atherosclerosis is an inflammatory disorder of the vascular wall and circulating immune cells such as monocytes/macrophages. Mice deficient in the low density lipoprotein (LDL) receptor (<i>Ldlr−/−</i>) fed on a high cholesterol diet (HCD) show elevated blood cholesterol levels and are widely used as models to study human atherosclerosis. In this study, we generated <i>Ldlr</i> and <i>Cebpe</i> double-knockout (<i>llee</i>) mice and compared their atherogenic phenotypes to <i>Ldlr</i> single deficient (<i>llEE</i>) mice after HCD. Macrophages from <i>llee</i> mice have reduced lipid uptake by foam cells and impaired phagokinetic motility <i>in vitro</i> compared to macrophages from <i>llEE</i> mice. Also, compared to <i>llEE</i> mice, <i>llee</i> mice have alterations of lipid metabolism, and reduced atheroma and obesity, particularly the males. Peritoneal macrophages of <i>llee</i> male mice have reduced mRNA expression of FABP4, a fatty acid binding protein implicated in atherosclerosis. Overall, our study suggests that the myeloid specific factor C/EBPε is involved in systemic lipid metabolism and that silencing of C/EBPε could decrease the development of atherosclerosis.</p>