C/EBP in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis.
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BACKGROUND AND OBJECTIVE: Atherosclerosis is both a chronic inflammatory disease and a lipid metabolism disorder. C/EBP is well documented for its role in the development of hematopoietic cells and integration of lipid metabolism. However, C/EBP's role in atherosclerotic progression has not been examined. We assessed the impact of hematopoietic CEBP deletion in ApoE(-/-) mice on hyperlipidemia, inflammatory responses and lesion formation in the aorta. METHODS AND RESULTS: ApoE(-/-) mice were reconstituted with bone marrow cells derived from either WT or C/EBP(-/-) mice and placed on low fat or high fat/high cholesterol diet for 11 weeks. Hematopoietic C/EBP deletion in ApoE(-/-) mice reduced blood and hepatic lipids and gene expression of hepatic stearoyl CoA desaturase 1 and fatty acid synthase while expression of ATP binding cassette transporter G1, cholesterol 7-alpha-hydroxylase, and liver X receptor alpha genes were significantly increased. ApoE(-/-) mice reconstituted with C/EBP(-/-) bone marrow cells also significantly reduced blood cytokine levels and reduced lesion area in aortic sinuses compared with ApoE(-/-) mice reconstituted with WT bone marrow cells. Silencing of C/EBP in RAW264.7 macrophage cells prevented oxLDL-mediated foam cell formation and inflammatory cytokine secretion in conditioned medium. CONCLUSION: C/EBP in hematopoietic cells is crucial to regulate diet-induced inflammation, hyperlipidemia and atherosclerosis development.
