Niacin reduces plasma CETP levels by diminishing liver macrophage content in CETP transgenic mice
Niacin reduces plasma CETP levels by diminishing liver macrophage content in CETP transgenic mice
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DOI：
10.1016/j.bcp.2012.06.020
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发表时间：
2012-09-15
影响因子：
5.8
通讯作者：
Hoekstra, Menno
中科院分区：
文献类型：
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作者：
Li, Zhaosha;Wang, Yanan;Hoekstra, Menno
抗血脂异常药物烟酸最近被证明可以降低CETP的肝脏表达和血浆水平。由于肝脏巨噬细胞有助于肝脏CETP表达，我们研究了巨噬细胞在烟酸降低小鼠CETP作用中的作用。体外研究表明，烟酸不会直接减弱巨噬细胞中CETP的表达。用烟酸喂养西方型饮食4周的血脂正常的人CETP转基因小鼠的治疗显著降低了肝胆固醇浓度（~ 20%）、肝CETP基因表达（~ 20%）和血浆CETP质量（~ 30%）。同时，烟酸降低了CD 68（-44%）和ABCG 1（-32%）的肝脏表达，这两种表达都是肝脏巨噬细胞含量的特异性标志物。肝脏CETP表达的减少与肝脏巨噬细胞标志物的减少显著相关。此外，烟酸减弱了致动脉粥样硬化饮食诱导的肝脏炎症，如TNF-α表达降低（~ 43%）所示。烟酸同样降低了高脂血症APOE*3-Leiden.CETP转基因小鼠的巨噬细胞标志物和绝对巨噬细胞含量。总之，烟酸通过减弱肝脏炎症和巨噬细胞含量来降低肝脏CETP表达和血浆CETP质量，而不是通过减弱巨噬细胞CETP表达水平来响应其主要降脂作用。(C)2012 Elsevier Inc. All rights reserved.
The anti-dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of CETP. Since liver macrophages contribute to hepatic CETP expression, we investigated the role of macrophages in the CETP-lowering effect of niacin in mice. In vitro studies showed that niacin does not directly attenuate CETP expression in macrophages. Treatment of normolipidemic human CETP transgenic mice, fed a Western-type diet with niacin for 4 weeks, significantly reduced the hepatic cholesterol concentration (-20%), hepatic CETP gene expression (-20%), and plasma CETP mass (-30%). Concomitantly, niacin decreased the hepatic expression of CD68 (-44%) and ABCG1 (-32%), both of which are specific markers for the hepatic macrophage content. The decrease in hepatic CETP expression was significantly correlated with the reduction of hepatic macrophage markers. Furthermore, niacin attenuated atherogenic diet-induced inflammation in liver, as evident from decreased expression of TNF-alpha (-43%). Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic APOE*3-Leiden.CETP transgenic mice on a Western-type diet. In conclusion, niacin decreases hepatic CETP expression and plasma CETP mass by attenuating liver inflammation and macrophage content in response to its primary lipid-lowering effect, rather than by attenuating the macrophage CETP expression level. (C) 2012 Elsevier Inc. All rights reserved.