Niemann-Pick C1 like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis
Niemann-Pick C1 like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis
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DOI：
10.1074/jbc.m405817200
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发表时间：
2004-08-06
影响因子：
4.8
通讯作者：
Altmann, SW
中科院分区：
文献类型：
--
作者：
Davis, HR;Zhu, LJ;Altmann, SW
尼曼-匹克C1样1（NPC 1 L1）是一种定位于空肠肠上皮细胞的蛋白质，对肠道胆固醇吸收至关重要。肠内植物甾醇和胆固醇被吸收到肠内的吸收性肠上皮细胞中的摄取在分子水平上还没有完全确定，并且NPC 1 L1在维持全身胆固醇稳态中的作用尚不清楚。NPC 1 L1基因敲除小鼠肠道对胆固醇和谷甾醇的摄取显著降低，血浆植物甾醇水平显著降低。NPC 1 L1基因敲除小鼠对饮食诱导的高胆固醇血症完全耐受，血浆脂蛋白和肝脏胆固醇谱与胆固醇吸收抑制剂依折麦布治疗的野生型小鼠相似。胆固醇/胆酸盐喂养导致野生型小鼠肠道NPC 1 L1 mRNA表达下调。NPC 1 L1缺陷导致肠羟甲基戊二酰辅酶A合成酶mRNA上调和肠胆固醇合成增加，ABCA 1 mRNA下调，ABCG 5和ABCG 8 mRNA表达无变化。NPC 1 L1是肠道摄取胆固醇和植物甾醇所必需的，并在胆固醇稳态中起主要作用。因此，NPC 1 L1可能是治疗高胆固醇血症和谷甾醇血症的有用的药物靶标。
Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.