Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein
Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein
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DOI：
10.1002/hep.24772
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发表时间：
2012-03-01
期刊：
影响因子：
13.5
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Yamanashi, Yoshihide;Takada, Tappei;Suzuki, Hiroshi
尼曼-匹克C1样1（NPC 1 L1）是肠道胆固醇吸收的关键分子，其在人类肝脏中的表达很高。除了NPC 1 L1，尼曼-匹克C2（NPC 2），一种参与细胞内胆固醇运输和刺激胆汁胆固醇分泌的分泌性胆固醇结合蛋白，也在肝脏中表达。在这项研究中，我们研究了NPC 1 L1和NPC 2之间的分子相互作用和功能关联。基于腺病毒或质粒介导的基因转移系统的体外研究显示，NPC 1 L1负调控NPC 2的蛋白表达和分泌，而不影响NPC 2信使RNA的水平。针对NPC 1 L1的小干扰RNA实验证实了这些蛋白质的内源性关联。此外，在NPC 1 L1过表达的细胞中，内吞的NPC 2可以补偿NPC 2的减少，这表明NPC 2的转录后调节依赖于NPC 1 L1抑制NPC 2成熟和加速NPC 2成熟过程中降解的新能力。此外，为了证实NPC 1 L1介导的调节的生理相关性，我们分析了人类肝脏标本，发现肝脏NPC 1 L1和肝脏NPC 2的蛋白水平之间呈负相关。结论：NPC 1 L1通过抑制NPC 2的成熟和加速其降解，下调NPC 2的表达和分泌。NPC 2作为细胞内胆固醇运输和胆汁胆固醇分泌的调节剂发挥作用;因此，除了其在肝细胞从胆汁中再摄取胆固醇中的作用外，肝NPC 1 L1可以通过下调NPC 2来控制胆固醇稳态。（肝脏学2011）
The hepatic expression of Niemann-Pick C1-like 1 (NPC1L1), which is a key molecule in intestinal cholesterol absorption, is high in humans. In addition to NPC1L1, Niemann-Pick C2 (NPC2), a secretory cholesterol-binding protein involved in intracellular cholesterol trafficking and the stimulation of biliary cholesterol secretion, is also expressed in the liver. In this study, we examined the molecular interaction and functional association between NPC1L1 and NPC2. In vitro studies with adenovirus-based or plasmid-mediated gene transfer systems revealed that NPC1L1 negatively regulated the protein expression and secretion of NPC2 without affecting the level of NPC2 messenger RNA. Experiments with small interfering RNA against NPC1L1 confirmed the endogenous association of these proteins. In addition, endocytosed NPC2 could compensate for the reduction of NPC2 in NPC1L1-overexpressing cells, and this demonstrated that the posttranscriptional regulation of NPC2 was dependent on a novel ability of NPC1L1 to inhibit the maturation of NPC2 and accelerate the degradation of NPC2 during its maturation. Furthermore, to confirm the physiological relevance of NPC1L1-mediated regulation, we analyzed human liver specimens and found a negative correlation between the protein levels of hepatic NPC1L1 and hepatic NPC2. Conclusion: NPC1L1 down-regulates the expression and secretion of NPC2 by inhibiting its maturation and accelerating its degradation. NPC2 functions as a regulator of intracellular cholesterol trafficking and biliary cholesterol secretion; therefore, in addition to its role in cholesterol re-uptake from the bile by hepatocytes, hepatic NPC1L1 may control cholesterol homeostasis via the down-regulation of NPC2. (HEPATOLOGY 2011)