C/EBPβ in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis

Abstract

Background and Objective Atherosclerosis is both a chronic inflammatory disease and a lipid metabolism disorder. C/EBPβ is well documented for its role in the development of hematopoietic cells and integration of lipid metabolism. However, C/EBPβ's role in atherosclerotic progression has not been examined. We assessed the impact of hematopoietic CEBPβ 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/EBPβ−/− mice and placed on low fat or high fat/high cholesterol diet for 11 weeks. Hematopoietic C/EBPβ 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/EBPβ−/− 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/EBPβ in RAW264.7 macrophage cells prevented oxLDL-mediated foam cell formation and inflammatory cytokine secretion in conditioned medium. Conclusion C/EBPβ in hematopoietic cells is crucial to regulate diet-induced inflammation, hyperlipidemia and atherosclerosis development.

PKCη deficiency improves lipid metabolism and atherosclerosis in apolipoprotein E‐deficient mice

“…Apoe −/− mice reconstituted with C/EBP β‐deficient bone marrow cells exhibited lower levels of serum LDL cholesterol and reduced atherosclerotic lesions compared with Apoe −/− mice reconstituted with wild‐type bone marrow cells (Rahman et al . ). They also showed that C/EBP β deficiency in Raw264.7 macrophage cells prevented oxidized LDL‐mediated foam cell formation and inflammatory cytokine production.…”

C/EBPβ Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1β Production by Macrophages

“…Generally, C/EBPβ was first found as a key regulator of IL-6 production [20]. Other studies have indicated that C/EBPβ may play important roles in the regulation of other inflammatory factors, such as IL-1β, MCP-1 and TNF-α [19]. However, the mechanisms by which C/EBPβ regulates inflammatory factors in macrophages, such as IL-1β production, in macrophages are still obscure.…”

“…C/EBPβ is a basic Leucine Zipper (bZIP) transcription factor which binds to certain DNA regulatory regions to regulate gene expression [18]. Knockout of C/EBPβ gene in mice shows significant reduction of inflammatory cytokine levels and lesion areas in aortic sinuses compared with wildtype mice [19]. Generally, C/EBPβ was first found as a key regulator of IL-6 production [20].…”

Haematopoietic-expressed C/EBPβ: A novel transcriptional regulator of hepatic liver metabolism and macrophage foam cells during atherosclerosis?

“…The paper by Rahman et al published in this issue of Atherosclerosis has identified a novel role for CCAAT/enhancer-binding protein b (C/EBPb) in atherosclerosis [5]. C/EBPb is a member of the basic leucine zipper family of transcription factors that is highly expressed in myelomonocytic cells and macrophages, and is increasingly recognised as an important regulator of monocyte/ macrophage activities [6e8].…”

“…In light of the implications of C/EBPb for macrophage function and lipid metabolism, Rahman et al have investigated for the first time the role of haematopoietic-expressed C/EBPb in atherosclerosis [5]. This study reports that reconstitution of irradiated ApoE À/ À mice fed a high-fat, high-cholesterol diet for 11 weeks with bone marrow from C/EBPb À/À mice resulted in (i) a significant reduction in circulating levels of LDL cholesterol and pro-inflammatory cytokines (TNF, IL-1b, Il-6, MCP-1), (ii) a >50% decrease in hepatic lipid levels that correlated with a reduction in fatty acid synthetic enzymes and increase in cholesterol metabolic and efflux genes, and (iii) an approximately 2-fold reduction in atherosclerotic lesion size at the aortic sinus (examination of how C/EBPb deficiency impacts on atherosclerosis at the aortic arch or more distal sites was not reported).…”