Sallam Tamer, Ito Ayaka, Rong Xin, Kim Jason, van Stijn Caroline, Chamberlain Brian T, Jung Michael E, Chao Lily C, Jones Marius, Gilliland Thomas, Wu XiaoHui, Su Grace L, Tangirala Rajendra K, Tontonoz Peter, Hong Cynthia
Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
J Lipid Res. 2014 Jun;55(6):1120-30. doi: 10.1194/jlr.M047548. Epub 2014 Mar 26.
The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation. We sought to identify previously unknown genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. Here we characterize a novel LXR target gene, the lipopolysaccharide binding protein (LBP) gene. Surprisingly, the ability of LXRs to control LBP expression is cell-type specific, occurring in macrophages but not liver. Treatment of macrophages with oxysterols or loading with modified LDL induces LBP in an LXR-dependent manner, suggesting a potential role for LBP in the cellular response to cholesterol overload. To investigate this further, we performed bone marrow transplant studies. After 18 weeks of Western diet feeding, atherosclerotic lesion burden was assessed revealing markedly smaller lesions in the LBP(-/-) recipients. Furthermore, loss of bone marrow LBP expression increased apoptosis in atherosclerotic lesions as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Supporting in vitro studies with isolated macrophages showed that LBP expression does not affect cholesterol efflux but promotes the survival of macrophages in the setting of cholesterol loading. The LBP gene is a macrophage-specific LXR target that promotes foam cell survival and atherogenesis.
肝脏X受体（LXRs）是核受体超家族的成员，可调节甾醇代谢和炎症反应。我们试图鉴定巨噬细胞中由LXRs调控的此前未知的基因，并确定它们在动脉粥样硬化形成中的作用。在此，我们描述了一种新的LXR靶基因——脂多糖结合蛋白（LBP）基因。令人惊讶的是，LXRs控制LBP表达的能力具有细胞类型特异性，在巨噬细胞中存在，而在肝脏中不存在。用氧化甾醇处理巨噬细胞或用修饰的低密度脂蛋白（LDL）负载巨噬细胞，以LXR依赖的方式诱导LBP表达，提示LBP在细胞对胆固醇过载的反应中具有潜在作用。为进一步研究这一点，我们进行了骨髓移植研究。在给予西方饮食18周后，评估动脉粥样硬化病变负荷，结果显示LBP基因敲除（LBP(-/-)）受体小鼠的病变明显更小。此外，通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色确定，骨髓LBP表达缺失增加了动脉粥样硬化病变中的细胞凋亡。对分离的巨噬细胞进行的体外研究支持了上述结果，表明LBP表达不影响胆固醇流出，但在胆固醇负载情况下可促进巨噬细胞存活。LBP基因是一种巨噬细胞特异性的LXR靶基因，可促进泡沫细胞存活和动脉粥样硬化形成。
