LXR Agonism Upregulates the Macrophage ABCA1/Syntrophin Protein Complex That Can Bind ApoA-I and Stabilized ABCA1 Protein, but Complex Loss Does Not Inhibit Lipid Efflux

Abstract

Macrophage ABCA1 effluxes lipid and has anti-inflammatory activity. The syntrophins, which are cytoplasmic PDZ protein scaffolding factors, can bind ABCA1 and modulate its activity. However, many or “much” of the data assessing the function of the ABCA1–syntrophin interaction are based on overexpression in nonmacrophage cells. To assess endogenous complex function in macrophages, we derived immortalized macrophages from Abca1+/+ and Abca1−/− mice and show their phenotype recapitulates primary macrophages. Abca1+/+ lines express the CD11B and F4/80 macrophage markers and markedly upregulate cholesterol efflux in response to LXR nuclear hormone agonists. In contrast, immortalized Abca1−/− macrophages show no efflux to apoA-I. In response to LPS, Abca1−/− macrophages display pro-inflammatory changes, including an increased level of expression of cell surface CD14, and 11–26-fold higher levels of IL-6 and IL-12 mRNA. Given recapitulation of phenotype, we show with these lines that the ABCA1–syntrophin protein complex is upregulated by LXR agonists and can bind apoA-I. Moreover, in immortalized macrophages, combined α1/β2-syntrophin loss modulated ABCA1 cell surface levels and induced pro-inflammatory gene expression. However, loss of all three syntrophin isoforms known to bind ABCA1 did not impair lipid efflux in immortalized or primary macrophages. Thus, the ABCA1–syntrophin protein complex is not essential for ABCA1 macrophage lipid efflux but does directly interact with apoA-I and can modulate the pool of cell surface ABCA1 stabilized by apoA-I.

Transcriptome profiling of antiviral immune and dietary fatty acid dependent responses of Atlantic salmon macrophage-like cells

“…This investigation showed that sntb1 is induced (more than 5-fold increase) in pIC-treated salmon MLCs at 24 HPS. SNTB1 is documented to modulate mammalian macrophage lipid efflux [ 127 ], but its function in antiviral responses is not well-understood. The qPCR assays showed a slight up-regulation for optn in pIC-exposed salmon MLCs (1.5-fold); this was, however, a lower fold-change than that seen in the microarray results.…”

Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization

“…Furthermore, activation of LXR suppresses angiogenesis through induction of ApoD [ 47 ]. Activation of LXR leads to an increased expression of Abca1 [ 22 ] and Abcg1, proteins important for cholesterol efflux from cells [ 48 ]. In relation to inflammation, Ito et al showed that LXR inhibits NF-kB and MAPK signaling by disrupting membrane lipid organization through Abca1.…”

Cellular Responses to the Efferocytosis of Apoptotic Cells

“…Macrophages have multiple pathways by which these cholesterol efflux pumps can be induced. This includes the induction of ABCA1 transcription by LXR following apoptotic cell uptake ( 103 ). In parallel, signaling through the efferocytic receptor BAI1 induces a signaling through the BAI1/ELMO/Rac1 pathway that leads to upregulation of ABCA1 in an LXR-independent manner ( 104 ).…”

“…In parallel, signaling through the efferocytic receptor BAI1 induces a signaling through the BAI1/ELMO/Rac1 pathway that leads to upregulation of ABCA1 in an LXR-independent manner ( 104 ). Both the LXR-dependent and -independent pathways enable macrophages to export excess cholesterol absorbed during efferocytosis, thus maintaining cholesterol homeostasis within the cell and avoiding death of the efferocyte ( 103 , 104 ). The consequences of impaired cholesterol efflux can be dire.…”