Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels.
Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels.
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肠道NPC1L1作为肝胆固醇和血动动动脉粥样硬化脂蛋白水平的主要决定因素。
DOI：
10.1016/j.atherosclerosis.2014.09.036
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发表时间：
2014-12
期刊：
影响因子：
5.3
通讯作者：
Yu, Liqing
中科院分区：
文献类型：
--
作者：
Xie, Ping;Zhu, Hongling;Jia, Lin;Ma, Yinyan;Tang, Weiqing;Wang, Youlin;Xue, Bingzhong;Shi, Hang;Yu, Liqing
关键词：
肠道胆固醇吸收值与血浆低密度脂蛋白胆固醇（LDL-C）水平之间的相关性仍存在争议。 Niemann-Pick-C1-Like 1 (NPC1L1) 对于肠道胆固醇吸收至关重要，并且是胆固醇吸收抑制剂依折麦布的靶标。然而，NPC1L1 敲除小鼠或依折麦布的研究无法明确阐明这种相关性，因为 NPC1L1 表达并不局限于人类和小鼠的肠道。在这项研究中，我们试图从基因角度解决这个问题。我们开发了一种缺乏内源性 (NPC1L1) 和 LDL 受体 (LDLR) (DKO) 的小鼠模型，但仅在胃肠道中转基因表达人类 NPC1L1（DKO/L1IntOnly 小鼠）。我们的新模型消除了非肠 NPC1L1 对胆固醇稳态的潜在影响。我们发现人 NPC1L1 位于 DKO/L1IntOnly 小鼠的肠刷状缘膜上。胆固醇喂养以依折麦布敏感的方式诱导该膜下 NPC1L1 阳性囊泡的形成。与DKO小鼠相比，DKO/L1IntOnly小鼠的胆固醇吸收和血液/肝脏/胆汁胆固醇显着增加。血液胆固醇的增加仅限于极低密度脂蛋白 (VLDL) 和 LDL 部分，这与载脂蛋白 B100 和 B48 的分泌和血浆水平增加有关。此外，DKO/L1IntOnly 小鼠表现出粪便胆固醇排泄和胆固醇生成基因的肝/肠表达减少。依折麦布治疗实际上逆转了 DKO/L1IntOnly 小鼠中所有转基因相关的表型。我们对 DKO/L1IntOnly 小鼠的研究结果清楚地表明，NPC1L1 介导的胆固醇吸收是含载脂蛋白 B 的致动脉粥样硬化脂蛋白血液水平的主要决定因素，至少在小鼠中是这样。
The correlation between intestinal cholesterol absorption values and plasma low-density lipoprotein-cholesterol (LDL-C) levels remains controversial. Niemann-Pick-C1-Like 1 (NPC1L1) is essential for intestinal cholesterol absorption, and is the target of ezetimibe, a cholesterol absorption inhibitor. However, studies with NPC1L1 knockout mice or ezetimibe cannot definitively clarify this correlation because NPC1L1 expression is not restricted to intestine in humans and mice. In this study we sought to genetically address this issue. We developed a mouse model that lacks endogenous (NPC1L1) and LDL receptor (LDLR) (DKO), but transgenically expresses human NPC1L1 in gastrointestinal tract only (DKO/L1IntOnly mice). Our novel model eliminated potential effects of non-intestinal NPC1L1 on cholesterol homeostasis. We found that human NPC1L1 was localized at the intestinal brush border membrane of DKO/L1IntOnly mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1IntOnly mice showed significant increases in cholesterol absorption and blood/hepatic/biliary cholesterol. Increased blood cholesterol was restricted to very low-density lipoprotein (VLDL) and LDL fractions, which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48. Additionally, DKO/L1IntOnly mice displayed decreased fecal cholesterol excretion and hepatic/intestinal expression of cholesterologenic genes. Ezetimibe treatment virtually reversed all of the transgene-related phenotypes in DKO/L1IntOnly mice. Our findings from DKO/L1IntOnly mice clearly demonstrate that NPC1L1-mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B-containing atherogenic lipoproteins, at least in mice.
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DOI：
10.1161/01.atv.0000257627.40486.46
发表时间：
2007-04-01
影响因子：
8.7
作者：
Davis, Harry R., Jr.;Hoos, Lizbeth M.;Altmann, Scott W.
通讯作者：
Altmann, Scott W.
影响因子：
8.9
作者：
GRUNDY, SM
通讯作者：
GRUNDY, SM
影响因子：
8.7
作者：
Davis, HR;Compton, DS;Tetzloff, G
通讯作者：
Tetzloff, G
影响因子：
4.8
作者：
Davis, HR;Zhu, LJ;Altmann, SW
通讯作者：
Altmann, SW
影响因子：
15.9
作者：
Graf, GA;Li, WP;Hobbs, HH
通讯作者：
Hobbs, HH