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
详细信息 查看全文
- 作者：Norimasa Tamehiro ; Min Hi Park ; Victoria Hawxhurst ; Kamalpreet Nagpal ; Marv E. Adams ; Vassilis I. Zannis ; Douglas T. Golenbock ; Michael L. Fitzgerald
- 刊名：Biochemistry
- 出版年：2015
- 出版时间：November 24, 2015
- 年：2015
- 卷：54
- 期：46
- 页码：6931-6941
- 全文大小：600K
- ISSN：1520-4995
文摘
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 of the data assessing the function of the ABCA1鈥搒yntrophin interaction are based on overexpression in nonmacrophage cells. To assess endogenous complex function in macrophages, we derived immortalized macrophages from Abca1+/+ and Abca1鈥?鈥?/i> 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鈥?鈥?/i> macrophages show no efflux to apoA-I. In response to LPS, Abca1鈥?鈥?/i> macrophages display pro-inflammatory changes, including an increased level of expression of cell surface CD14, and 11鈥?6-fold higher levels of IL-6 and IL-12 mRNA. Given recapitulation of phenotype, we show with these lines that the ABCA1鈥搒yntrophin protein complex is upregulated by LXR agonists and can bind apoA-I. Moreover, in immortalized macrophages, combined 伪1/尾2-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鈥搒yntrophin 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.