An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues.
An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues.
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DOI：
10.1016/j.plipres.2021.101140
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发表时间：
2022-01
影响因子：
13.6
通讯作者：
Zhang K
中科院分区：
文献类型：
--
作者：
Zhang R;Zhang K
在哺乳动物中，甘油三酯（TG）是用于储存和提供能量的脂质的主要形式，在食物摄入后储存在白色脂肪组织（WAT）中，而在禁食期间，它被路由到氧化组织（心脏和骨骼肌）用于能量产生，该过程被称为TG分配。脂蛋白脂酶（LPL）是这一基本生理过程中的限速酶，它水解循环中的TG产生游离脂肪酸，这些游离脂肪酸被外周组织吸收。LPL的餐后活性在氧化组织中下降，但在WAT中上升，将TG引导到WAT;在禁食期间则相反。然而，在禁食周期中调节组织特异性LPL活性的分子机制尚未完全了解。对血管生成素样（ANGPTL）蛋白（A3、A4和A8）的研究已经产生了ANGPTL 3 -4-8模型来解释WAT和氧化组织之间的TG分配。食物摄入诱导肝脏和WAT中的A8表达。肝脏A8通过形成A3-8复合物激活A3，然后分泌到循环中。A3-8复合物以内分泌方式起作用以抑制氧化组织中的LPL。WAT A8形成A4-8复合物，其局部作用以阻断A4的LPL抑制活性。因此，餐后LPL活性在氧化组织中低，但在WAT中高，将循环TG引导至WAT。相反，在禁食期间，肝脏和WAT中A8表达的减少分别使A3不能抑制氧化组织LPL并恢复WAT A4的LPL抑制活性。因此，空腹LPL活性在氧化组织中高，但在WAT中低，将TG导向前者。未来对A3、A4和A8的研究有望为人类健康、疾病和治疗提供更多见解。
In mammals, triglyceride (TG), the main form of lipids for storing and providing energy, is stored in white adipose tissue (WAT) after food intake, while during fasting it is routed to oxidative tissues (heart and skeletal muscle) for energy production, a process referred to as TG partitioning. Lipoprotein lipase (LPL), a rate-limiting enzyme in this fundamental physiological process, hydrolyzes circulating TG to generate free fatty acids that are taken up by peripheral tissues. The postprandial activity of LPL declines in oxidative tissues but rises in WAT, directing TG to WAT; the reverse is true during fasting. However, the molecular mechanism in regulating tissue-specific LPL activity during the fed-fast cycle has not been completely understood. Research on angiopoietin-like (ANGPTL) proteins (A3, A4, and A8) has resulted in an ANGPTL3–4-8 model to explain the TG partitioning between WAT and oxidative tissues. Food intake induces A8 expression in the liver and WAT. Liver A8 activates A3 by forming the A3–8 complex, which is then secreted into the circulation. The A3–8 complex acts in an endocrine manner to inhibit LPL in oxidative tissues. WAT A8 forms the A4–8 complex, which acts locally to block A4’s LPL-inhibiting activity. Therefore, the postprandial activity of LPL is low in oxidative tissues but high in WAT, directing circulating TG to WAT. Conversely, during fasting, reduced A8 expression in the liver and WAT disables A3 from inhibiting oxidative-tissue LPL and restores WAT A4’s LPL-inhibiting activity, respectively. Thus, the fasting LPL activity is high in oxidative tissues but low in WAT, directing TG to the former. Future research on A3, A4, and A8 can hopefully provide more insights into human health, disease, and therapeutics.
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