The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice
The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice
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DOI：
10.1007/s00125-009-1611-5
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发表时间：
2010-03-01
期刊：
影响因子：
8.2
通讯作者：
Adeli, K.
中科院分区：
文献类型：
--
作者：
Hsieh, J.;Longuet, C.;Adeli, K.
胰高血糖素样肽1（GLP-1）受体（GLP-1 R）激动剂和二肽基肽酶-4（DPP-4）抑制剂通过尚不清楚的机制减轻餐后脂血症。由于血脂异常是2型糖尿病心血管疾病的一个危险因素，我们研究了GLP-1作用的药理学和生理学调节与餐后脂质代谢控制的机制，在正常和果糖喂养的仓鼠和野生型小鼠中评估了餐后脂质合成和分泌，这些小鼠接受或不接受西格列汀治疗。载脂蛋白B-48（Apo B-48）的合成和分泌也在原代肠上皮细胞培养物中进行了检查。在用GLP-1 R激动剂exendin-4、GLP-1 R拮抗剂exendin（9-39）处理的小鼠和仓鼠中以及在Glp 1 r（+/+）与Glp 1 r（-/-）小鼠中评估了外源性与内源性GLP-1 R信号传导对调节肠道脂蛋白合成和分泌的重要性。西格列汀降低空腹血浆三酰甘油，主要在VLDL组分中，以及仓鼠和小鼠中的餐后富含三酰甘油的脂蛋白（TRL）-三酰甘油、TRL-胆固醇和TRL-ApoB-48。单独使用exendin-4激活GLP-1 R也可降低仓鼠和小鼠的血浆和TRL-ApoB-48，并降低仓鼠肠细胞培养物中ApoB-48的分泌。相反，通过拮抗剂exendin（9-39）阻断内源性GLP-1 R信号传导或在Glp 1 r（-/-）小鼠中遗传消除GLP-1 R信号传导可增强体内TRL-ApoB-48分泌。同时给予exendin（9-39）也消除了西格列汀的降血脂作用。通过DPP-4抑制或GLP-1 R信号传导的药理学增强增强内源性肠促胰岛素作用，可减少三酰甘油、胆固醇和ApoB-48的肠道分泌。此外，内源性GLP-1 R信号传导对于控制肠脂蛋白生物合成和分泌至关重要。
Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors attenuate postprandial lipaemia through mechanisms that remain unclear. As dyslipidaemia is a contributing risk factor for cardiovascular disease in type 2 diabetes, we examined the mechanisms linking pharmacological and physiological regulation of GLP-1 action to control of postprandial lipid metabolism.Postprandial lipid synthesis and secretion were assessed in normal and fructose-fed hamsters and in wild-type mice that were treated with or without sitagliptin. Apolipoprotein B-48 (ApoB-48) synthesis and secretion were also examined in primary enterocyte cultures. The importance of exogenous vs endogenous GLP-1R signalling for regulation of intestinal lipoprotein synthesis and secretion was assessed in mice and hamsters treated with the GLP-1R agonist exendin-4, the GLP-1R antagonist exendin(9-39) and in Glp1r (+/+) vs Glp1r (-/-) mice.Sitagliptin decreased fasting plasma triacylglycerol, predominantly in the VLDL fraction, as well as postprandial triacylglycerol-rich lipoprotein (TRL)-triacylglycerol, TRL-cholesterol and TRL-ApoB-48 in hamsters and mice. GLP-1R activation with exendin-4 alone also decreased plasma and TRL-ApoB-48 in hamsters and mice, and reduced secretion of ApoB-48 in hamster enterocyte cultures. Conversely, blockade of endogenous GLP-1R signalling by the antagonist exendin(9-39) or genetic elimination of GLP-1R signalling in Glp1r (-/-) mice enhanced TRL-ApoB-48 secretion in vivo. Co-administration of exendin(9-39) also abolished the hypolipidaemic effect of sitagliptin.Potentiation of endogenous incretin action via DPP-4 inhibition or pharmacological augmentation of GLP-1R signalling reduces intestinal secretion of triacylglycerol, cholesterol and ApoB-48. Moreover, endogenous GLP-1R signalling is essential for the control of intestinal lipoprotein biosynthesis and secretion.