PPARγ1 and LXRα face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1

Abstract

Peroxisome proliferator-activated receptor γ1 (PPARγ1) and liver X receptor α (LXRα) are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation; key biological processes in atherogenesis. The activation of PPARγ1 and LXRα 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. Control of PPARs and LXRs transcriptional activity by coactivators and corepressors is also highlighted. The specific roles that PPARγ1 and LXRα play in inducing macrophage cholesterol efflux mediators and antagonizing macrophage inflammatory responsiveness are summarized. Finally, this review focuses on the recently reported regulatory functions that adipocyte enhancer-binding protein 1 (AEBP1) exerts on PPARγ1 and LXRα transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation.

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

“…In this study, we observed that oxLDL induced the expression of UFM1 in human primary monocytes and THP-1 cells. These from its imperative role in controlling macrophage cholesterol homeostasis 45,46) . Interestingly, pretreatment with LXR siRNA dramatically reversed the UFM1-induced reduction of p roinflammatory cytokine secretion, consistent with a recent report by Majdalawieh et al 55) .…”

“…Because ABCG1 and ABCA1 are regulated by the nuclear receptor LXR [43][44][45][46] , we further examined whether the key transcription factor LXR is involved in the UFM1-induced expression of ABCA1 and ABCG1. First, we detected the LXR expression in LV-UFM1 and sh-UFM macrophages by western blot analysis.…”

“…Once activated, LXRs induce an array of genes that are involved in cholesterol absorption, efflux, transport, and secretion 45,46) . Previous reports have suggested that ABCA1 and ABCG1 are LXR target gene s, and LXR -mediated transcriptional regulation is required for inducing these cholesterol transporters 34,53) .…”

Pigment Epithelium-derived Factor (PEDF) Promotes Tumor Cell Death by Inducing Macrophage Membrane Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

“…PPAR␥ heterodimerizes with the 9-cis-retinoic acid receptor (RXR) to form a transcription factor that binds to peroxisome proliferator response elements (PPREs) in the promoter region of target genes (30). PPAR␥ modulates many functions of macrophages, such as promoting cell differentiation (31), regulating cholesterol homeostasis (32), and antagonizing expression of proinflammatory genes (32,33). Recent findings indicate that PPAR␥ activation functions as a signaling mechanism for the anti-angiogenesis and anti-inflammatory function of PEDF (34,35).…”

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

“…Our findings strongly suggest that macrophage AEBP1 plays a critical role in the development of atherosclerosis. The potential pro-atherogenic properties of AEBP1 may be a byproduct of a vital interplay of its ability to antagonize PPARγ1 and LXRα cholesterol efflux functions in macrophages and its ability to promote inflammation via enhanced NF-κB transcriptional activity (39,40). We anticipate that AEBP1 may serve as a molecular candidate toward the development of therapeutic strategies to ameliorate or attenuate atherogenesis.…”