Angiopoietin-like protein 4(E40K) and ANGPTL4/8 complex have reduced, temperature-dependent LPL-inhibitory activity compared to ANGPTL4
Angiopoietin-like protein 4(E40K) and ANGPTL4/8 complex have reduced, temperature-dependent LPL-inhibitory activity compared to ANGPTL4
复制标题
DOI：
10.1016/j.bbrc.2020.11.053
复制
发表时间：
2021-01-01
影响因子：
3.1
通讯作者：
Konrad, Robert J.
中科院分区：
文献类型：
--
作者：
Chen, Yan Q.;Pottanat, Thomas G.;Konrad, Robert J.
我们之前证明，血管生成素样 8 (ANGPTL8) 与 ANGPTL4 形成局部复合物，以降低其脂蛋白脂肪酶 (LPL) 抑制活性，并增加餐后脂肪组织对脂肪酸 (FA) 的摄取。由于长时间的寒冷暴露可能会通过降低 ANGPTL4 表达和诱导 ANGPTL8 表达（进而诱导 ANGPTL4/8 表达）来增加脂肪组织 FA 摄取并降低循环甘油三酯 (TG)，因此我们在体外研究了温度对 ANGPTL4 和 ANGPTL4/8 LPL 抑制活性的影响。由于 ANGPTL4(E40K) 突变导致 TG 降低，我们还表征了 ANGPTL4(E40K) 和 ANGPTL4(E40K)/8 复合物 LPL 抑制活性。有趣的是，虽然ANGPTL3、ANGPTL3/8和ANGPTL4在37℃和22℃下表现出相似的LPL抑制作用，但ANGPTL4/8在37℃下已经降低的LPL抑制活性在22℃下甚至降低得更多。在37℃下，ANGPTL4(E40K)表现出与相比，ANGPTL4(E40K)的LPL抑制活性降低。 ANGPTL4/8，而ANGPTL4(E40K)/8的效力甚至进一步降低。值得注意的是，ANGPTL4/8、ANGPTL4(E40K) 和 ANGPTL4(E40K)/8 实际上都能够在 22 摄氏度下刺激 LPL 活性。 总之，这些结果表明，ANGPTL4/8 在低温下刺激 LPL 活性可能代表了在冷暴露期间进一步增加脂肪组织 FA 摄取的另一种机制，除了由于 ANGPTL4 表达减少和 ANGPTL8 表达增加而已经发生的机制之外。此外，由于与 ANGPTL4/8 相比，ANGPTL4(E40K) 降低了 LPL 抑制活性，因此我们的研究结果还表明了为什么 ANGPTL4(E40K) 携带者循环 TG 水平降低。 (C) 2020 Elsevier Inc. 保留所有权利。
We previously demonstrated that angiopoietin-like 8 (ANGPTL8) forms a localized complex with ANGPTL4 to reduce its lipoprotein lipase (LPL)-inhibitory activity and enable increased postprandial uptake of fatty acids (FA) into adipose tissue. Because prolonged cold exposure may increase adipose tissue FA uptake and decrease circulating triglycerides (TG) by reducing ANGPTL4 expression and inducing ANGPTL8 expression (and thus ANGPTL4/8 expression), we investigated the effect of temperature on ANGPTL4 and ANGPTL4/8 LPL-inhibitory activities in vitro. As the ANGPTL4(E40K) mutation results in decreased TG, we also characterized ANGPTL4(E40K) and ANGPTL4(E40K)/8 complex LPL-inhibitory activities. Interestingly, while ANGPTL3, ANGPTL3/8, and ANGPTL4 showed similar LPL inhibition at 37 degrees C and 22 degrees C, the already reduced LPL-inhibitory activity of ANGPTL4/8 at 37 degrees C was even more decreased at 22 degrees C. At 37 degrees C, ANGPTL4(E40K) manifested decreased LPL-inhibitory activity compared to ANGPTL4/8, while ANGPTL4(E40K)/8 had even further reduced potency. Remarkably, ANGPTL4/8, ANGPTL4(E40K), and ANGPTL4(E40K)/8 were each actually capable of stimulating LPL activity at 22 degrees C. Together, these results indicate that ANGPTL4/8 stimulation of LPL activity at low temperatures may represent an additional mechanism for further increasing adipose tissue FA uptake during cold exposure, beyond that already occurring due to decreased ANGPTL4 expression and increased ANGPTL8 expression. In addition, because ANGPTL4(E40K) has decreased LPL-inhibitory activity compared to ANGPTL4/8, our findings also suggest why ANGPTL4(E40K) carriers have decreased circulating TG levels. (C) 2020 Elsevier Inc. All rights reserved.