College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China; Department of Animal and Avian Science, University of Maryland, College Park, MD, 20742, USA.
Department of Animal and Avian Science, University of Maryland, College Park, MD, 20742, USA; The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China.
Biochem Biophys Res Commun. 2018 May 15;499(3):626-633. doi: 10.1016/j.bbrc.2018.03.200. Epub 2018 Mar 31.
Niemann-Pick C1-like1 (NPC1L1), a crucial cholesterol absorption receptor expressed in human intestine and liver. But in mouse it is only expressed in intestine. Previous studies elucidated that expression of human NPC1L1 in mouse liver led to increase of plasma cholesterol due to activation of absorption from bile. However, hepatic NPC1L1 function was not elucidated in LDL receptor deficient mouse (LDLR-/-) in which LDL was a main lipoprotein as in human.
L1-Tg/LDLR-/- mouse was created by crossing liver-specific NPC1L1 transgenic mouse (L1-Tg) with LDLR-/-. L1-Tg/LDLR-/- mice developed hyperlipidemia when fed with atherogenic diet (AD) containing 0.2% cholesterol for 21days. Compared with control mice, biliary cholesterol level in L1-Tg/LDLR-/- mice was significantly lower, plasma cholesterol level was significantly higher in L1-Tg/LDLR-/- mice under both chow diet and AD feeding. New finding in this study is augmentations of plasma TAG L1-Tg/LDLR-/- mice fed with AD. Results were shown that very low density lipoprotein (VLDL) secretion was elevated in L1-Tg/LDLR-/- mice after AD fed. The increase of VLDL secretion was further confirmed by higher expression of hepatic triacylglycerol hydrolase (TGH) and microsomal triglyceride transfer protein (MTP).
L1-Tg/LDLR-/- mouse is a humanized model to study cholesterol absorption and transportation. The results obtained from L1-Tg/LDLR-/- mouse indicated no feedback mechanism to inhibit NPC1L1 function in liver and hepatic expression of NPC1L1 correlated with VLDL secretion in hypercholesterolemia state.
尼曼-皮克 C1 样 1（NPC1L1）是一种在人体肠道和肝脏中表达的重要胆固醇吸收受体。然而，在小鼠中，它仅在肠道中表达。先前的研究表明，在 LDL 受体缺失（LDLR-/-）小鼠的肝脏中表达人 NPC1L1 会由于激活胆汁中的吸收而导致血浆胆固醇增加。然而，在 LDL 是主要脂蛋白的情况下，在 LDLR-/-小鼠中尚未阐明肝 NPC1L1 的功能。
通过将肝特异性 NPC1L1 转基因小鼠（L1-Tg）与 LDLR-/-杂交，创建了 L1-Tg/LDLR-/-小鼠。当用含有 0.2%胆固醇的动脉粥样硬化饮食（AD）喂养 21 天时，L1-Tg/LDLR-/-小鼠会发生高脂血症。与对照小鼠相比，L1-Tg/LDLR-/-小鼠的胆汁胆固醇水平明显较低，在正常饮食和 AD 喂养下，L1-Tg/LDLR-/-小鼠的血浆胆固醇水平明显较高。本研究的新发现是，在 AD 喂养下，L1-Tg/LDLR-/-小鼠的血浆 TAG 水平增加。结果表明，在 AD 喂养后，L1-Tg/LDLR-/-小鼠的极低密度脂蛋白（VLDL）分泌增加。肝三酰甘油水解酶（TGH）和微粒体甘油三酯转移蛋白（MTP）的高表达进一步证实了 VLDL 分泌的增加。
L1-Tg/LDLR-/-小鼠是研究胆固醇吸收和转运的人源化模型。从 L1-Tg/LDLR-/-小鼠获得的结果表明，肝脏中 NPC1L1 功能没有反馈抑制机制，肝 NPC1L1 的表达与高胆固醇血症状态下的 VLDL 分泌相关。
