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Apolipoprotein A5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition.
Journal of Lipid Research ( IF 6.5 ) Pub Date : 2021-03-21 , DOI: 10.1016/j.jlr.2021.100068
Yan Q Chen 1 , Thomas G Pottanat 2 , Eugene Y Zhen 1 , Robert W Siegel 1 , Mariam Ehsani 1 , Yue-Wei Qian 1 , Robert J Konrad 1
Affiliation  

Triglyceride (TG) molecules represent the major storage form of fatty acids, and TG metabolism is essential to human health. However, the mechanistic details surrounding TG metabolism are complex and incompletely elucidated. While it is known that angiopoietin-like protein 8 (ANGPTL8) increases TG through an ANGPTL3/8 complex that inhibits lipoprotein lipase (LPL), the mechanism governing apolipoprotein A5 (ApoA5), which lowers TG, has remained elusive. Current hypotheses for how ApoA5 acts include direct stimulation of LPL, facilitation of TG-containing particle uptake, and regulation of hepatic TG secretion. Using immunoprecipitation-mass spectrometry and Western blotting, bio-layer interferometry, functional LPL enzymatic assays, and kinetic analyses of LPL activity, we show that ApoA5 associates with ANGPTL3/8 in human serum and most likely decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition. We also demonstrate that ApoA5 has no direct effect on LPL, nor does it suppress the LPL-inhibitory activities of ANGPTL3, ANGPTL4, or ANGPTL4/8. Importantly, ApoA5 suppression of ANGPTL3/8-mediated LPL inhibition occurred at a molar ratio consistent with the circulating concentrations of ApoA5 and ANGPTL3/8. Because liver X-receptor (LXR) agonists decrease ApoA5 expression and cause hypertriglyceridemia, we investigated the effect of the prototypical LXR agonist T0901317 on human primary hepatocytes. We observed that T0901317 modestly stimulated hepatocyte ApoA5 release, but markedly stimulated ANGPTL3/8 secretion. Interestingly, the addition of insulin to T0901317 attenuated ApoA5 secretion, but further increased ANGPTL3/8 secretion. Together, these results reveal a novel intersection of ApoA5 and ANGPTL3/8 in the regulation of TG metabolism and provide a possible explanation for LXR agonist-induced hypertriglyceridemia.

中文翻译:

载脂蛋白 A5 通过抑制 ANGPTL3/8 介导的 LPL 抑制来降低甘油三酯水平。

甘油三酯(TG)分子代表了脂肪酸的主要储存形式,TG代谢对人体健康至关重要。然而,围绕 TG 代谢的机制细节很复杂,而且尚未完全阐明。虽然已知血管生成素样蛋白 8 (ANGPTL8) 通过抑制脂蛋白脂肪酶 (LPL) 的 ANGPTL3/8 复合物增加 TG,但控制载脂蛋白 A5 (ApoA5) 降低 TG 的机制仍然难以捉摸。目前关于 ApoA5 如何发挥作用的假设包括直接刺激 LPL、促进含 TG 颗粒的摄取和调节肝脏 TG 分泌。使用免疫沉淀-质谱法和蛋白质印迹法、生物层干涉法、功能性 LPL 酶测定法和 LPL 活性的动力学分析,我们表明 ApoA5 与人血清中的 ANGPTL3/8 相关,并且很可能通过抑制 ANGPTL3/8 介导的 LPL 抑制来降低 TG。我们还证明 ApoA5 对 LPL 没有直接影响,也不会抑制 ANGPTL3、ANGPTL4 或 ANGPTL4/8 的 LPL 抑制活性。重要的是,ApoA5 抑制 ANGPTL3/8 介导的 LPL 抑制的摩尔比与 ApoA5 和 ANGPTL3/8 的循环浓度一致。因为肝 X 受体 (LXR) 激动剂降低 ApoA5 表达并导致高甘油三酯血症,我们研究了原型 LXR 激动剂 T0901317 对人原代肝细胞的影响。我们观察到 T0901317 适度刺激肝细胞 ApoA5 释放,但显着刺激 ANGPTL3/8 分泌。有趣的是,在 T0901317 中添加胰岛素会减弱 ApoA5 的分泌,但进一步增加了ANGPTL3/8的分泌。总之,这些结果揭示了 ApoA5 和 ANGPTL3/8 在调节 TG 代谢中的新交集,并为 LXR 激动剂诱导的高甘油三酯血症提供了可能的解释。
更新日期:2021-03-29
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