AEBP1 is a Novel Oncogene: Mechanisms of Action and Signaling Pathways.

Adipocyte enhancer-binding protein 1 (AEBP1) is a transcriptional repressor involved in the regulation of critical biological processes including adipogenesis, mammary gland development, inflammation, macrophage cholesterol homeostasis, and atherogenesis. Several years ago, we first reported the ability of AEBP1 to exert a positive control over the canonical NF-B pathway. Indeed, AEBP1 positively regulates NF-B activity via its direct interaction with IB, a key NF-B inhibitor.

Sesamol and sesame (Sesamum indicum) oil enhance macrophage cholesterol efflux via up-regulation of PPARγ1 and LXRα transcriptional activity in a MAPK-dependent manner.

Purpose: Cholesterol clearance by macrophages is a vital process to eliminate excess cholesterol from the body. Internalization of modified cholesterol by macrophages triggers overexpression of peroxisome proliferator-activated receptor γ1 (PPARγ1) and liver X receptor α (LXRα), two transcription factors that are critically involved in macrophage cholesterol efflux. Recent studies demonstrate that oral administration of sesamol derivative (INV-403) and sesame oil leads to a significant attenuation of atherosclerosis in Watanabe heritable hyperlipidemic rabbits and LDLR(-/-) mice, respectively.

The anti-atherogenic properties of sesamin are mediated via improved macrophage cholesterol efflux through PPARγ1-LXRα and MAPK signaling.

Background: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARγ1 and LXRα, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood.

Stromal adipocyte enhancer-binding protein (AEBP1) promotes mammary epithelial cell hyperplasia via proinflammatory and hedgehog signaling.

Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression.

Lactation defect with impaired secretory activation in AEBP1-null mice.

Adipocyte enhancer binding protein 1 (AEBP1) is a multifunctional protein that negatively regulates the tumor suppressor PTEN and IκBα, the inhibitor of NF-κB, through protein-protein interaction, thereby promoting cell survival and inflammation. Mice homozygous for a disrupted AEBP1 gene developed to term but showed defects in growth after birth. AEBP1(-/-) females display lactation defect, which results in the death of 100% of the litters nursed by AEBP1(-/-) dams.

Adipocyte enhancer-binding protein 1 (AEBP1) (a novel macrophage proinflammatory mediator) overexpression promotes and ablation attenuates atherosclerosis in ApoE (-/-) and LDLR (-/-) mice.

Atherogenesis is a long-term process that involves inflammatory response coupled with metabolic dysfunction. Foam cell formation and macrophage inflammatory response are two key events in atherogenesis. Adipocyte enhancer-binding protein 1 (AEBP1) has been shown to impede macrophage cholesterol efflux, promoting foam cell formation, via peroxisome proliferator-activated receptor (PPAR)-γ1 and liver X receptor α (LXRα) downregulation.

PPARgamma1 and LXRalpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1.

Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation; key biological processes in atherogenesis. The activation of PPARgamma1 and LXRalpha by natural or synthetic ligands results in the transactivation of ABCA1, ABCG1, and ApoE; integral players in cholesterol efflux and reverse cholesterol transport. In this review, we describe the structure, isoforms, expression pattern, and functional specificity of PPARs and LXRs.

Regulation of IkappaBalpha function and NF-kappaB signaling: AEBP1 is a novel proinflammatory mediator in macrophages.

NF-kappaB comprises a family of transcription factors that are critically involved in various inflammatory processes. In this paper, the role of NF-kappaB in inflammation and atherosclerosis and the regulation of the NF-kappaB signaling pathway are summarized. The structure, function, and regulation of the NF-kappaB inhibitors, IkappaBalpha and IkappaBbeta, are reviewed.

LPS-induced suppression of macrophage cholesterol efflux is mediated by adipocyte enhancer-binding protein 1.

Macrophages facilitate clearance of cholesterol from the body via reverse cholesterol transport (RCT). The first event in RCT is internalization of modified low density lipoprotein by macrophages, upon which PPARgamma1 and LXRalpha signaling pathways are turned on, leading to the transactivation of a cascade of genes (e.g.

The trans-10, cis-12 isomer of conjugated linoleic acid decreases adiponectin assembly by PPARgamma-dependent and PPARgamma-independent mechanisms.

The adipocyte-derived secretory protein adiponectin functions as an insulin-sensitizing agent. In plasma, adiponectin exists as low, medium, and high molecular weight oligomers. Treatment with trans-10, cis-12 conjugated linoleic acid (t-10, c-12 CLA) reduces levels of adiponectin as well as triglyceride (TG) in mice and adipocyte cell culture models.

Adipocyte enhancer-binding protein 1 modulates adiposity and energy homeostasis.

Objective: To determine whether adipocyte enhancer binding protein (AEBP) 1, a transcriptional repressor that is down-regulated during adipogenesis, functions as a critical regulator of adipose tissue homeostasis through modulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) tumor suppressor activity and mitogen-activated protein kinase (MAPK) activation.

Research Methods And Procedures: We examined whether AEBP1 physically interacts with PTEN in 3T3-L1 cells by coimmunoprecipitation analysis. We generated AEBP1-null mice and examined the physiological role of AEBP1 as a key modulator of in vivo adiposity.

Adipocyte enhancer-binding protein-1 promotes macrophage inflammatory responsiveness by up-regulating NF-kappaB via IkappaBalpha negative regulation.

Nuclear factor kappaB (NF-kappaB) subunits comprise a family of eukaryotic transcription factors that are critically involved in cell proliferation, inflammation, and apoptosis. Under basal conditions, NF-kappaB subunits are kept under inhibitory regulation by physical interaction with NF-kappaB inhibitors (IkappaB subunits) in the cytosol. Upon stimulation, IkappaB subunits become phosphorylated, ubiquitinated, and subsequently degraded, allowing NF-kappaB subunits to translocate to the nucleus and bind as dimers to kappaB responsive elements of target genes.

Modeling and functional analysis of AEBP1, a transcriptional repressor.

Adipocyte enhancer binding protein 1 (AEBP1) is a transcriptional repressor of the aP2 gene, which encodes the adipocyte lipid binding protein and is involved in the differentiation of preadipocytes into mature adipocytes. It is an isoform of aortic carboxypeptidase-like protein (ACLP), which is a part of the extracellular matrix. AEBP1 and ACLP contain a conserved carboxypeptidase domain which is critical for the function of AEBP1 as a transcriptional repressor.

Adipocyte enhancer-binding protein 1 is a potential novel atherogenic factor involved in macrophage cholesterol homeostasis and inflammation.

Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) play pivotal roles in macrophage cholesterol homeostasis and inflammation, key biological processes in atherogenesis. Herein we identify adipocyte enhancer-binding protein 1 (AEBP1) as a transcriptional repressor that impedes macrophage cholesterol efflux, promoting foam cell formation, via PPARgamma1 and LXRalpha down-regulation. Contrary to AEBP1 deficiency, AEBP1 overexpression in macrophages is accompanied by decreased expression of PPARgamma1, LXRalpha, and their target genes ATP-binding cassette A1, ATP-binding cassette G1, apolipoprotein E, and CD36, with concomitant elevation in IL-6, TNF-alpha, monocyte chemoattractant protein 1, and inducible NO synthase levels.

The role of AEBP1 in sex-specific diet-induced obesity.

Obesity is an important risk factor for heart disease, diabetes, and certain cancers, but the molecular basis for obesity is poorly understood. The transcriptional repressor AEBP1, which functions as a negative regulator of PTEN through a protein-protein interaction, is highly expressed in the stromal compartment of adipose tissues, including proliferative preadipocytes, and its expression is abolished in terminally differentiated, nonproliferative adipocytes. Here we show that transgenic overexpression of AEBP1 during adipogenesis coupled with a high-fat diet (HFD) resulted in massive obesity in female transgenic (AEBP1(TG)) mice via adipocyte hyperplasia.

MAPK modulates the DNA binding of adipocyte enhancer-binding protein 1.

Adipocyte enhancer-binding protein 1 (AEBP1) is a down-regulator of adipogenesis through its transcriptional repression activity, as well as through its interaction with mitogen-activated protein kinase (MAPK), which protects MAPK from its specific phosphatases. This study increases our understanding of the mechanisms of DNA binding by AEBP1, the first step in its function as a transcriptional repressor. We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding.