Glucagon like receptor 1/ glucagon dual agonist acutely enhanced hepatic lipid clearance and suppressed de novo lipogenesis in mice
Glucagon like receptor 1/ glucagon dual agonist acutely enhanced hepatic lipid clearance and suppressed de novo lipogenesis in mice
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DOI：
10.1371/journal.pone.0186586
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发表时间：
2017-10-24
期刊：
影响因子：
3.7
通讯作者：
Carrington, Paul
中科院分区：
文献类型：
--
作者：
More, Vijay R.;Lao, Julie;Carrington, Paul
已有文献报道了胰升糖素的降血脂作用。阻断高血糖素信号会导致血浆低密度脂蛋白水平升高。在这里，我们展示了急性剂量的GLP1R/GCGR双激动剂(DualAG)的降脂效果。所有实验都是在25周龄雄性饮食诱导的(60%大卡脂肪)肥胖小鼠上进行的。禁食2小时后，皮下注射赋形剂、利拉鲁肽(25nmol/kg)和双乙醇胺(25nmoL/kg)。用D2O掺入法测定胆固醇和棕榈酸酯的从头合成。用C-13(18)-油酸盐输注测定脂肪酸酯化反应。同时激活GLP1R和GCGR可降低血浆甘油三酯和胆固醇水平。DualAG可提高肝脏LDLR蛋白水平，降低血浆ApoB48和ApoB100含量。急性DualAG治疗后，极低密度脂蛋白的分泌、棕榈酸酯的从头合成和脂肪酸的酯化反应减少。另一方面，DualAG治疗后酮体水平升高，表明脂肪酸氧化增加。利拉鲁肽治疗组未见血脂相关改变。在一次急性治疗中，DualAG显示了对脂质平衡的显著影响，特别是对肝脏摄取、VLDL分泌和从头合成的影响。这些效应共同揭示了DualAG的降脂作用主要是通过胰高血糖素信号，以肝脏为中心的。
Lipid lowering properties of glucagon have been reported. Blocking glucagon signaling leads to rise in plasma LDL levels. Here, we demonstrate the lipid lowering effects of acute dosing with Glp1r/Gcgr dual agonist (DualAG). All the experiments were performed in 25 week-old male diet-induced (60% kCal fat) obese mice. After 2 hrs of fasting, mice were injected subcutaneously with vehicle, liraglutide (25nmol/kg) and DualAG (25nmol/kg). De novo cholesterol and palmitate synthesis was measured by deuterium incorporation method using D2O. C-13(18)-oleate infusion was used for measuring fatty acid esterification. Simultaneous activation of Glp1r and Gcgr resulted in decrease in plasma triglyceride and cholesterol levels. DualAG enhanced hepatic LDLr protein levels, along with causing decrease in content of plasma ApoB48 and ApoB100. VLDL secretion, de novo palmitate synthesis and fatty acid esterification decreased with acute DualAG treatment. On the other hand, ketone levels were elevated with DualAG treatment, indicating increased fatty acid oxidation. Lipid relevant changes were absent in liraglutide treated group. In an acute treatment, DualAG demonstrated significant impact on lipid homeostasis, specifically on hepatic uptake, VLDL secretion and de novo synthesis. These effects collectively reveal that lipid lowering abilities of DualAG are primarily through glucagon signaling and are liver centric.