A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase.
A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase.
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DOI：
10.1038/srep18502
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发表时间：
2015-12-21
影响因子：
4.6
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Fu Z;Abou-Samra AB;Zhang R
Lipasin/Angptl 8是一种调节甘油三酯（TAG）代谢的摄食诱导的肝细胞因子;然而，其治疗潜力、作用机制以及与脂蛋白脂肪酶（LPL）的关系仍然难以捉摸。我们制备了五种单克隆脂蛋白酶抗体，其中一种在注射到小鼠体内时降低血清TAG水平，并且确定表位为EIQVEE。脂肪酶缺乏小鼠的心脏和骨骼肌中LPL的餐后活性升高，但在白色脂肪组织（WAT）中没有，表明脂肪酶抑制LPL的活性，特别是在心脏和骨骼肌中。一致地，注射有效抗体或脂肪酶缺乏的小鼠仅在进食状态下具有增加的餐后心脏LPL活性和较低的TAG水平。这些结果表明，脂蛋白酶的行为，至少部分，在内分泌方式。我们提出了以下模型：进食诱导脂蛋白酶，激活脂蛋白酶-Angptl 3途径，其抑制心脏和骨骼肌中的LPL以将循环TAG引导至WAT用于储存;相反，禁食诱导Angptl 4，其抑制WAT中的LPL以将循环TAG引导至心脏和骨骼肌用于氧化。该模型表明TAG运输在不同营养状态下由脂蛋白酶、Angptl 3和Angptl 4协调的一般机制。
Lipasin/Angptl8 is a feeding-induced hepatokine that regulates triglyceride (TAG) metabolism; its therapeutical potential, mechanism of action, and relation to the lipoprotein lipase (LPL), however, remain elusive. We generated five monoclonal lipasin antibodies, among which one lowered the serum TAG level when injected into mice, and the epitope was determined to be EIQVEE. Lipasin-deficient mice exhibited elevated postprandial activity of LPL in the heart and skeletal muscle, but not in white adipose tissue (WAT), suggesting that lipasin suppresses the activity of LPL specifically in cardiac and skeletal muscles. Consistently, mice injected with the effective antibody or with lipasin deficiency had increased postprandial cardiac LPL activity and lower TAG levels only in the fed state. These results suggest that lipasin acts, at least in part, in an endocrine manner. We propose the following model: feeding induces lipasin, activating the lipasin-Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles to direct circulating TAG to WAT for storage; conversely, fasting induces Angptl4, which inhibits LPL in WAT to direct circulating TAG to cardiac and skeletal muscles for oxidation. This model suggests a general mechanism by which TAG trafficking is coordinated by lipasin, Angptl3 and Angptl4 at different nutritional statuses.