Adipocyte Enhancer-binding Protein-1 Promotes Macrophage Inflammatory Responsiveness by Up-Regulating NF-κB via IκBα Negative Regulation

Abstract

Nuclear factor B (NF-B) subunits comprise a family of eukaryotic transcription factors that are critically involved in cell proliferation, inflammation, and apoptosis. Under basal conditions, NF-B subunits are kept under inhibitory regulation by physical interaction with NF-B inhibitors (IB subunits) in the cytosol. Upon stimulation, IB subunits become phosphorylated, ubiquitinated, and subsequently degraded, allowing NF-B subunits to translocate to the nucleus and bind as dimers to B responsive elements of target genes. Previously, we have shown that AEBP1 enhances macrophage inflammatory responsiveness by inducing the expression of various proinflammatory mediators. Herein, we provide evidence suggesting that AEBP1 manifests its proinflammatory function by up-regulating NF-B activity via hampering IB␣, but not IB␤, inhibitory function through protein-protein interaction mediated by the discoidin-like domain (DLD) of AEBP1. Such interaction renders IB␣ susceptible to enhanced phosphorylation and degradation, subsequently leading to augmented NF-B activity. Collectively, we propose a novel molecular mechanism whereby NF-B activity is modulated by means of protein-protein interaction involving AEBP1 and IB␣. Moreover, our study provides a plausible mechanism explaining the differential regulatory functions exhibited by IB␣ and IB␤ in various cell types. We speculate that AEBP1 may serve as a potential therapeutic target for the treatment of various chronic inflammatory diseases and cancer.

Genomics of Adaptation to Multiple Concurrent Stresses: Insights from Comparative Transcriptomics of a Cichlid Fish from One of Earth’s Most Extreme Environments, the Hypersaline Soda Lake Magadi in Kenya, East Africa

“…Nevertheless, most of the positively selected genes in our study are associated with physiological functions related to stress (Table 4). AEBP1 (dN/dS 2.167) plays a key role in apoptosis and cell survival by facilitating enhanced macrophage inflammatory responsiveness (Majdalawieh et al 2007). Under extreme environmental stress, the immune system of fish is greatly compromised, and thus, genes with functions related to immune response such as AEBP1 are expected to be under strong positive selection in stressful environments.…”

Adipocyte Enhancer-Binding Protein 1 (AEBP1) (a Novel Macrophage Proinflammatory Mediator) Overexpression Promotes and Ablation Attenuates Atherosclerosis in ApoE−/− and LDLR−/− Mice

“…Recently, AEBP1 was shown to be abundantly expressed in primary macro phages and macrophage cell lines (9)(10)(11). We demonstrated that AEBP1 represses the expression of PPARγ1 and LXRα in a dose-dependent, DNA binding-dependent fashion, which is accompanied by concurrent repression of major cholesterol efflux mediators (for example, ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1) and apolipoprotein [Apo]-E), leading to foam cell formation (9).…”

“…We demonstrated that AEBP1 represses the expression of PPARγ1 and LXRα in a dose-dependent, DNA binding-dependent fashion, which is accompanied by concurrent repression of major cholesterol efflux mediators (for example, ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1) and apolipoprotein [Apo]-E), leading to foam cell formation (9). AEBP1 was also shown to promote macrophage inflammatory responsiveness by inducing nuclear factor (NF)-κB activity via IκBα-negative regulation through protein-protein interaction (10). These experimental findings strongly suggest that AEBP1 may exert potent atherogenic effects in vivo.…”

Stromal Adipocyte Enhancer-binding Protein (AEBP1) Promotes Mammary Epithelial Cell Hyperplasia via Proinflammatory and Hedgehog Signaling

“…Adipocyte enhancer-binding protein 1 (AEBP1) is a novel proinflammatory mediator (19) that induces NF-B activity via hampering IB␣ inhibitory function (20). AEBP1 is expressed in many tissues, but it is most abundant in preadipocytes (21,22) and macrophages (19,20,23), which are found in mammary stroma.…”

“…AEBP1 is expressed in many tissues, but it is most abundant in preadipocytes (21,22) and macrophages (19,20,23), which are found in mammary stroma. We have recently demonstrated that AEBP1 is specifically localized in the stromal compartment of adult nulliparous mammary glands and that macrophage AEBP1 plays a critical role in mammary gland development (24).…”