NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy
NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy
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DOI：
10.1126/scitranslmed.3010329
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发表时间：
2015-02-18
影响因子：
17.1
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Takada, Tappei;Yamanashi, Yoshihide;Suzuki, Hiroshi
维生素K （VK）是一种促进血液凝固的微量营养素。VK拮抗剂，如华法林，在临床上用于预防血栓栓塞。由于VK不能在体内合成，因此其肠道吸收对于维持全身VK水平至关重要。然而，这种吸收的分子机制尚不清楚。我们证明了Niemann-Pick C1-like 1 （NPC1L1）蛋白，一种胆固醇转运蛋白，在肠道VK摄取中起核心作用，并调节华法林的抗凝作用。利用过表达npc1l1的肠道细胞和敲除npc1l1的小鼠进行的体外研究表明，肠道VK吸收依赖于npc1l1，并被依zetimibe（一种临床用于治疗血脂异常的npc1l1选择性抑制剂）抑制。此外，体内药理学研究表明，依zetimibe和华法林合用可降低肝脏VK水平，增强华法林的药理作用。ezetimibe和华法林共同使用引起的不良事件通过口服VK补充得以缓解，这表明观察到的药物-药物相互作用效应是ezetimibe介导的VK吸收不良的结果。这一机制得到了临床数据回顾性评估的支持，该评估显示，在85%以上的华法林治疗患者中，与依折麦布联合治疗可以增强抗凝血活性。我们的发现对VK吸收的分子机制提供了深入的了解。依折替米贝（一种胆固醇转运抑制剂）和华法林（一种VK拮抗剂和抗凝剂）之间的这种新的药物-药物相互作用机制可以通过改变必需的脂溶性维生素的动力学，为使用这些药物的患者提供临床护理信息。
Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins.