Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux
Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux
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DOI：
10.1194/jlr.m067025
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发表时间：
2016-07-01
影响因子：
6.5
通讯作者：
Reddy, Srinivasa T.
中科院分区：
文献类型：
--
作者：
Meriwether, David;Sulaiman, Dawoud;Reddy, Srinivasa T.
apoA-I模拟肽4F的作用位点和机制尚不完全清楚。经肠胆固醇流出（TICE）是一个涉及清除体内多余胆固醇的过程。虽然TICE负责至少30%的中性固醇从循环进入肠腔的清除，但已鉴定出很少的药理学试剂调节该途径。我们首先表明，循环4F选择性地靶向小肠（SI），它主要被转运到肠腔。4F进入SI腔的这种运输本质上是经肠的，并且它由TICE调节。我们还表明，循环4F增加胆固醇从巨噬细胞的反向转运和胆固醇流出脂蛋白通过TICE途径。我们确定的原因，这种调制的TICE作为4F是胆固醇受体相对于肠上皮细胞，4F增强胆固醇流出，或作为4F是肠伴侣相对于TICE。我们的研究结果为4F分配了一个新的角色，作为TICE通路的调节剂，并表明4F的抗炎功能可能是4F和胆固醇共同依赖的肠道转运的部分结果。Meriwether，D.，D. Sulaiman，A.瓦格纳，V. Grijalva，I. Kaji，K.威廉姆斯湖放大图片作者：C. Volpe，S. J. Bensinger，G. M.阿南塔拉玛雅岛Shechter，A. M. Fogelman和S. T.雷迪抗炎药物4F的经肠转运和胆固醇经肠流出的调节。
The site and mechanism of action of the apoA-I mimetic peptide 4F are incompletely understood. Transintestinal cholesterol efflux (TICE) is a process involved in the clearance of excess cholesterol from the body. While TICE is responsible for at least 30% of the clearance of neutral sterols from the circulation into the intestinal lumen, few pharmacological agents have been identified that modulate this pathway. We show first that circulating 4F selectively targets the small intestine (SI) and that it is predominantly transported into the intestinal lumen. This transport of 4F into the SI lumen is transintestinal in nature, and it is modulated by TICE. We also show that circulating 4F increases reverse cholesterol transport from macrophages and cholesterol efflux from lipoproteins via the TICE pathway. We identify the cause of this modulation of TICE either as 4F being a cholesterol acceptor with respect to enterocytes, from which 4F enhances cholesterol efflux, or as 4F being an intestinal chaperone with respect to TICE. Our results assign a novel role for 4F as a modulator of the TICE pathway and suggest that the anti-inflammatory functions of 4F may be a partial consequence of the co-dependent intestinal transport of both 4F and cholesterol.-Meriwether, D., D. Sulaiman, A. Wagner, V. Grijalva, I. Kaji, K. J. Williams, L. Yu, Spencer Fogelman, C. Volpe, S. J. Bensinger, G. M. Anantharamaiah, I. Shechter, A. M. Fogelman, and S. T. Reddy. Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux.