The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking.
The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking.
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ANGPTL3-4-8 模型，甘油三酯运输的分子机制。
DOI：
10.1098/rsob.150272
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发表时间：
2016-04
期刊：
影响因子：
5.8
通讯作者：
Zhang R
中科院分区：
文献类型：
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作者：
Zhang R
脂蛋白脂酶（LPL）是一种限速酶，可将循环中的甘油三酯（TG）水解为游离脂肪酸，并被外周组织吸收。餐后LPL活性在白色脂肪组织（WAT）中升高，但在心脏和骨骼肌中下降，从而将循环TG引导至WAT进行储存;在禁食期间则相反。然而，组织特异性调节LPL活性的机制在进食-禁食周期一直难以捉摸。最近对脂肪酶/血管生成素样8（Angptl 8）（一种摄食诱导的肝细胞因子）以及Angptl 3和Angptl 4的鉴定提供了有趣但令人困惑的见解，因为所有三个Angptl成员都是LPL抑制剂，并且任何一个的缺乏（过表达）都会导致低血糖症（高血糖症）。那么，为什么自然界需要这三种力量呢？我们最近关于Angptl 8在心肌和骨骼肌中特异性负调节LPL活性的数据提示了Angptl 3 -4-8模型：进食诱导Angptl 8，激活Angptl 8-Angptl 3途径，其抑制心肌和骨骼肌中的LPL，从而使循环TG可用于WAT摄取，其中LPL活性由于Angptl 4减少而升高;在禁食期间，情况正好相反，禁食抑制Angpt 18，但诱导Angpt 14，从而将TG引导至肌肉。该模型提出了一个如何监管转基因生物贩运的总体框架。
Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed–fast cycle has been elusive. Recent identification of lipasin/angiopoietin-like 8 (Angptl8), a feeding-induced hepatokine, together with Angptl3 and Angptl4, provides intriguing, yet puzzling, insights, because all the three Angptl members are LPL inhibitors, and the deficiency (overexpression) of any one causes hypotriglyceridaemia (hypertriglyceridaemia). Then, why does nature need all of the three? Our recent data that Angptl8 negatively regulates LPL activity specifically in cardiac and skeletal muscles suggest an Angptl3-4-8 model: feeding induces Angptl8, activating the Angptl8–Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating TG available for uptake by WAT, in which LPL activity is elevated owing to diminished Angptl4; the reverse is true during fasting, which suppresses Angptl8 but induces Angptl4, thereby directing TG to muscles. The model suggests a general framework for how TG trafficking is regulated.