Transgenic angiopoietin-like (Angptl)4 overexpression and targeted disruption of Angptl4 and Angptl3:: Regulation of triglyceride metabolism
Transgenic angiopoietin-like (Angptl)4 overexpression and targeted disruption of Angptl4 and Angptl3:: Regulation of triglyceride metabolism
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DOI：
10.1210/en.2005-0476
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发表时间：
2005-11-01
期刊：
影响因子：
4.8
通讯作者：
Eacho, P
中科院分区：
文献类型：
--
作者：
Köster, A;Chao, YB;Eacho, P
脂蛋白脂酶（LPL）是甘油三酯清除的关键调节因子。它在进食和禁食期间的协调调节对于维持脂质稳态和能量供应至关重要。血管生成素样（Angpt 1）3和Angpt 14是已被证明通过抑制LPL来调节甘油三酯代谢的分泌蛋白。我们已经采取了靶向遗传方法来产生Angpt 14和Angpt 13缺陷小鼠以及在肝脏中过表达人Angpt 14的转基因小鼠。Angpt 14转基因小鼠显示血浆甘油三酯升高和肝素后血浆（PHP）LPL活性降低。纯化的重组Angpt 14蛋白在体外抑制小鼠LPL和重组人LPL活性。与转基因小鼠相反，Angpt 14缺陷小鼠表现出低血糖和PHP LPL活性增加，与进食状态相比，禁食状态下的影响更大。Angpt 13缺陷小鼠也表现出低血糖，PHP LPL活性升高，但这些小鼠在进食状态下表现出更大的影响。两种Angpt 1蛋白缺陷的小鼠显示出对血浆甘油三酯的累加效应，并且不能存活超过2个月。我们的研究结果表明，Angpt 13和Angpt 14在不同营养状态下调节循环甘油三酯水平，因此通过对LPL的差异抑制在进食/禁食期间的脂质代谢中发挥作用。
Lipoprotein lipase (LPL) is a key regulator of triglyceride clearance. Its coordinated regulation during feeding and fasting is critical for maintaining lipid homeostasis and energy supply. Angiopoietin-like (Angpt1)3 and Angpt14 are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angpt14- and Angpt13-deficient mice as well as transgenic mice overexpressing human Angpt14 in the liver. The Angpt14 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma (PHP) LPL activity. A purified recombinant Angpt14 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angpt14-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angpt13-deficient mice also displayed hypotriglyceridemia with elevated PHP LPL activity, but these mice showed a greater effect in the fed state. Mice deficient in both Angpt1 proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angpt13 and Angpt14 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.