Honzumi Shoko, Shima Akiko, Hiroshima Ayano, Koieyama Tadashi, Terasaka Naoki
Biological Research Laboratories, Daiichi Sankyo Co, Tokyo, Japan.
Biochim Biophys Acta. 2011 Dec;1811(12):1136-45. doi: 10.1016/j.bbalip.2011.08.009. Epub 2011 Aug 19.
The nuclear receptors Liver X receptors, LXRα and LXRβ, regulate cholesterol and triglyceride metabolism. We and others have previously reported that synthetic LXR agonists reduced atherosclerosis in models of mouse with no detectable plasma cholesteryl ester transfer protein (CETP) activity, which plays an important role in reverse cholesterol transport. In the present study, we investigated the effect of LXR activation in rabbits to elucidate the influence of CETP activity. First, we cloned rabbit LXRs cDNA. The data indicated that rabbit LXRα was mostly highly expressed in the liver, whereas LXRβ expression was ubiquitous. Next, we investigated the effect of LXR agonist on lipid levels. Treatment with LXR agonist T0901317 increased plasma CETP activity and consequently elevated LDL, but no change in HDL. High cholesterol (HC) diet-feeding, which is thought to provide oxysterols as the natural agonists, could also increase expression of CETP and other LXR target genes. Finally, we tested T0901317 in the atherosclerosis intervention study. Chronic administration of T0901317 significantly reduced atherosclerosis in HC diet-fed rabbits despite less favorable lipid profiles, i.e. increases of plasma triglycerides and no change of HDL. T0901317 induced ATP-binding cassette transporters ABCA1 and ABCG1 and suppressed inflammatory genes expression in the aorta, suggesting that direct actions of LXR agonist on vascular gene expression are likely to contribute to the antiatherogenic effect. The present work strongly supports the idea that LXR agonists could be beneficial as therapeutic agents for treatment of atherosclerosis.
核受体肝X受体（LXRα和LXRβ）调节胆固醇和甘油三酯代谢。我们和其他研究人员之前曾报道，在血浆中检测不到胆固醇酯转运蛋白（CETP）活性的小鼠模型中，合成的LXR激动剂可减轻动脉粥样硬化，而CETP在逆向胆固醇转运中起重要作用。在本研究中，我们研究了LXR激活对兔的影响，以阐明CETP活性的作用。首先，我们克隆了兔LXRs的cDNA。数据表明，兔LXRα在肝脏中表达最高，而LXRβ的表达则较为广泛。接下来，我们研究了LXR激动剂对血脂水平的影响。用LXR激动剂T0901317治疗可增加血浆CETP活性，从而升高低密度脂蛋白（LDL），但高密度脂蛋白（HDL）无变化。高胆固醇（HC）饮食被认为可提供氧化甾醇作为天然激动剂，也可增加CETP和其他LXR靶基因的表达。最后，我们在动脉粥样硬化干预研究中测试了T0901317。尽管血脂情况不太理想，即血浆甘油三酯升高而HDL无变化，但长期给予T0901317可显著减轻HC饮食喂养兔的动脉粥样硬化。T0901317诱导ATP结合盒转运蛋白ABCA1和ABCG1，并抑制主动脉中炎症基因的表达，这表明LXR激动剂对血管基因表达的直接作用可能有助于其抗动脉粥样硬化作用。目前的研究有力地支持了LXR激动剂作为治疗动脉粥样硬化的治疗药物可能有益的观点。
