Amin Majdalawieh
Faculty of Arts & Sciences, United Arab Emirates
Title: Regulation of macrophage cholesterol homeostasis, inflammation and atherosclerosis by adipocyte enhancerbinding protein-1 (aebp1)
Biography
Biography: Amin Majdalawieh
Abstract
Atherogenesis is a long-term process involving inflammatory response and metabolic dysfunction. Adipocyte enhancer-binding protein-1 (AEBP1) impedes macrophage cholesterol efflux, promoting foam cell formation, via PPARβ1 and LXRβ down-regulation. The objective of this study is to assess the role of macrophage AEBP1 in atherogenesis and evaluate the effect of its over-expression and ablation on atherosclerotic lesion formation in mice. Atherogenesis and macrophage infiltration were assessed using AEBP1-/-/LDLR-/- double-knockout mice, en face analysis, bone marrow (BM) transplantation, and immunohistochemistry of aortic cryosections. mRNA and protein levels were assessed by real-time PCR and immunoblotting, respectively. AEBP1-transgenic mice (AEBP1TG) with macrophage-specific AEBP1 over-expression exhibit hyperlipidemia and develop atherosclerosis. Consistently, ablation of AEBP1 results in significant attenuation of atherosclerosis in the AEBP1-/-/LDLR-/- doubleknockout mice. BM transplantation experiments reveal that LDLR-/- mice reconstituted with AEBP1-/-/LDLR-/- BM cells (LDLR-/-/KO-BM chimera) display significant reduction of atherosclerosis lesions compared to control mice reconstituted with AEBP1+/+/LDLR-/- BM cells (LDLR-/-/WT-BM chimera). Furthermore, transplantation of AEBP1TG BM cells with normal ApoE gene into ApoE-/- mice (ApoE-/-/TG-BM chimera) leads to significant atherogenesis despite the restoration of ApoE expression. Macrophages from ApoE-/-/TG-BM chimeric mice express reduced levels of PPARβ1, LXRβ, ABCA1 and ABCG1 and increased levels of the inflammatory mediators IL-6 and TNFβ compared to macrophages of control chimeric mice (ApoE- /-/NT-BM) that received AEBP1-non-transgenic (AEBP1NT) BM cells. Our in vivo experimental data strongly suggest that macrophage AEBP1 plays critical regulatory roles in atherogenesis. We anticipate that AEBP1 may serve as a potential therapeutic target for the treatment of atherosclerosis.