Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetirnibe
Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetirnibe
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DOI：
10.1172/jci30060
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Yu, Liqing
中科院分区：
文献类型：
--
作者：
Temel, Ryan E.;Tang, Weiqing;Yu, Liqing
尼曼-匹克Cl样I（NPC 1 L1）是胆固醇吸收所必需的。肠NPC 1 L1似乎是依折麦布的靶点，依折麦布是一种胆固醇吸收抑制剂，可有效降低人体血浆LDL-胆固醇。然而，人类肝脏也表达NPC 1 L1。NPC 1 L1的肝功能以前是未知的，但我们最近发现，NPC 1 L1定位于灵长类动物肝细胞的小管膜，NPC 1 L1促进肝癌细胞的胆固醇摄取。基于这些发现，我们假设肝NPC 1 L1允许肝细胞保留胆汁胆固醇，依折麦布破坏NPC 1 L1的肝功能。为了检验这一假设，建立了在肝细胞中表达人NPC 1 L1的转基因小鼠（L1-Tg小鼠）。肝脏过表达NPC 1 L1导致胆汁胆固醇浓度降低10- 20倍，但磷脂和胆汁酸浓度没有降低。这种降低与血浆胆固醇增加30%-60%有关，主要是因为富含apoE的HDL的积累。依折麦布给药后，这些动物的胆汁和血浆胆固醇浓度几乎恢复正常。这些结果表明，在人体中，依折麦布可能通过抑制肠和肝脏中的NPC 1 L1功能来降低血浆胆固醇，肝脏NPC 1 L1可能已经进化为保护身体免受胆固醇过度胆固醇损失。
Niemann-Pick Cl-like I (NPC1L1) is required for cholesterol absorption. Intestinal NPC1L1 appears to be a target of ezetimibe, a cholesterol absorption inhibitor that effectively lowers plasma LDL-cholesterol in humans. However, human liver also expresses NPC1L1. Hepatic function of NPC1L1 was previously unknown, but we recently discovered that NPC1L1 localizes to the canalicular membrane of primate hepatocytes and that NPC1L1 facilitates cholesterol uptake in hepatoma cells. Based upon these findings, we hypothesized that hepatic NPC1L1 allows the retention of biliary cholesterol by hepatocytes and that ezetimibe disrupts hepatic function of NPC1L1. To test this hypothesis, transgenic mice expressing human NPC1L1 in hepatocytes (L1-Tg mice) were created. Hepatic overexpression of NPC1L1 resulted in a 10- to 20-fold decrease in biliary cholesterol concentration, but not phospholipid and bile acid concentrations. This decrease was associated with a 30%-60% increase in plasma cholesterol, mainly because of the accumulation of apoE-rich HDL. Biliary and plasma cholesterol concentrations in these animals were virtually returned to normal with ezetimibe treatment. These findings suggest that in humans, ezetimibe may reduce plasma cholesterol by inhibiting NPC1L1 function in both intestine and liver, and hepatic NPC1L1 may have evolved to protect the body from excessive biliary loss of cholesterol.