dc.contributor.author | Majdalawieh, Amin F. | en_US |
dc.date.accessioned | 2014-10-21T12:37:25Z | |
dc.date.available | 2006 | |
dc.date.issued | 2006 | en_US |
dc.identifier.other | AAINR19605 | en_US |
dc.identifier.uri | http://hdl.handle.net/10222/54844 | |
dc.description | PPARgamma1 and LXRalpha are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation, key biological processes in atherogenesis. Once fully differentiated, intimal macrophages express scavenger receptors, allowing internalization of oxidized low density lipoprotein (oxLDL). PPARgamma1 and LXRalpha become activated in response to lipid loading, and they cooperate to induce expression of the cholesterol/phospholipid ATP-binding cassette (ABC) transporter proteins and apolipoprotein E (ApoE), prominent players in macrophage cholesterol efflux. Pro-inflammatory mediators such as interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) promote cell recruitment to the inflamed vasculature, advancing atherogenesis. | en_US |
dc.description | Adipocyte enhancer-binding protein 1 (AEBP1) is an 82-kDa, ubiquitously expressed transcriptional repressor that plays key regulatory roles in various biological processes. Herein, AEBP1 is identified as a transcriptional repressor that impedes macrophage cholesterol efflux via PPARgamma1 and LXRalpha down-regulation in a DNA binding-dependent manner. Contrary to AEBP1 deficiency (AEBP1-/-), AEBP1 transgenic over-expression (AEBP1 TG) in macrophages is accompanied by decreased expression of PPARgamma1 and LXRalpha, and their target genes ABCAl, ABCG1, apolipoprotem E, and CD36, with concomitant elevation in IL-6, TNFalpha, MCP-1, and iNOS levels. AEBP1-mediated repression of PPARgamma1 and LXRalpha is physiologically relevant since AEBP1TG macrophages accumulate considerable amounts of lipids compared to AEBP1 non-transgenic (AEBP1NT) macrophages, making them precursors for foam cells. Indeed, AEBP1TG and AEBP1-/- macrophages exhibit diminished and enhanced cholesterol efflux, respectively. Remarkably, AEBP1TG mice, but not AEBP1NT counterparts, exhibit hyperlipidemia and develop lipid-filled atherosclerosic lesions consisting of intimal macrophages in their proximal aortae, suggesting that AEBP1TG mice may serve as a novel murine model of atherosclerosis. | en_US |
dc.description | Experimental evidence suggests that AEBP1 manifests its pro-inflammatory function by up-regulating NF-kappaB activity via hampering IkappaBalpha inhibitory function through DLD-mediated protein-protein interaction, rendering IkappaBalpha susceptible to increased phosphorylation and proteolytic degradation, subsequently leading to augmented NF-kappaB transcriptional activity. Collectively, in vitro and ex vivo experimental evidence prompts speculation that AEBP1 may potentially function as a critical pro-inflammatory, pro-atherogenic mediator with the anticipation that it may serve as a molecular target for the development of therapeutic strategies towards the treatment of atherosclerosis and inflammatory diseases. | en_US |
dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2006. | en_US |
dc.language | eng | en_US |
dc.publisher | Dalhousie University | en_US |
dc.publisher | | en_US |
dc.subject | Biology, Molecular. | en_US |
dc.subject | Chemistry, Biochemistry. | en_US |
dc.title | Adipocyte enhancer-binding protein-1 (AEBP1) is a novel player in macrophage cholesterol homeostasis, inflammation, and atherogenesis. | en_US |
dc.type | text | en_US |
dc.contributor.degree | Ph.D. | en_US |