Liver-derived fibroblast growth factor 21 mediates effects of glucagon-like peptide-1 in attenuating hepatic glucose output
Liver-derived fibroblast growth factor 21 mediates effects of glucagon-like peptide-1 in attenuating hepatic glucose output
复制标题
肝源性成纤维细胞生长因子 21 介导胰高血糖素样肽-1 减弱肝葡萄糖输出的作用
DOI：
10.1016/j.ebiom.2019.02.037
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发表时间：
2019-03-01
期刊：
影响因子：
11.1
通讯作者：
Hong, Tianpei
中科院分区：
文献类型：
--
作者：
Liu, Junling;Yang, Kun;Hong, Tianpei
背景：胰高血糖素样肽-1（GLP-1）及其基剂改善血糖控制。尽管它们对肝葡萄糖输出的衰减作用几十年来吸引了我们的注意力，但潜在的机制仍然不清楚。方法：使用细胞因子阵列试剂盒评估DB/DB小鼠的细胞因子谱和小鼠原发性肝细胞用Exenatide处理（Exendin-4）。用GLP-1模拟床或liraglutide处理了两种糖尿病小鼠模型（DB/DB和PAX6（M/+））。测量了糖尿病小鼠，原代小鼠和人肝细胞的肝脏中成纤维细胞生长因子21（FGF21）的表达和分泌，并测量了使用或未使用GLP-1类似物处理的人肝细胞系HEPG2。使用中和抗体或siRNA或从FGF21敲除小鼠中分离出的FGF21的阻塞，并分析了关键酶在糖异生中的表达和活性。评估了接受体床治疗的2型糖尿病（T2D）患者的血清FGF21水平。调查：利用细胞因子阵列，我们确定FGF21的分泌被埃替尼（Exendin4）上调。类似地，艾替尼或liraglutide刺激肝细胞中的FGF21产生。 FGF21阻塞减弱了GLP-1类似物对肝葡萄糖输出的抑制作用。在FGF21敲除小鼠的原发性肝细胞中也观察到了类似的结果。此外，T2D患者的血清FGF21水平提高了血清FGF21水平，尤其是在葡萄糖控制较高的患者中。解释：我们通过肝激素FGF21介导GLP-1在抑制肝葡萄糖输出中的功能。因此，我们提供了一种新的胰腺外机制，通过该机制调节葡萄糖稳态。 （c）2019年作者。由Elsevier B.V.出版
Background: Glucagon-like peptide-1 (GLP-1) and its based agents improve glycemic control. Although their attenuating effect on hepatic glucose output has drawn our attention for decades, the potential mechanisms remain unclear.Methods: Cytokine array kit was used to assess cytokine profiles in db/db mice and mouse primary hepatocytes treated with exenatide (exendin-4). Two diabetic mouse models (db/db and Pax6(m/+)) were treated with a GLP-1 analog exenatide or liraglutide. The expression and secretion of fibroblast growth factor 21 (FGF21) in the livers of diabetic mice, primary mouse and human hepatocytes, and the human hepatic cell line HepG2 treated with or without GLP-1 analog were measured. Blockage of FGF21 with neutralizing antibody or siRNA, or hepatocytes isolated from Fgf21 knockout mice were used, and the expression and activity of key enzymes in gluconeogenesis were analyzed. Serum FGF21 level was evaluated in patients with type 2 diabetes (T2D) receiving exenatide treatment.Findings: Utilizing the cytokine array, we identified that FGF21 secretion was upregulated by exenatide (exendin4). Similarly, FGF21 production in hepatocytes was stimulated by exenatide or liraglutide. FGF21 blockage attenuated the inhibitory effects of the GLP-1 analogs on hepatic glucose output. Similar results were also observed in primary hepatocytes from Fgf21 knockout mice. Furthermore, exenatide treatment increased serum FGF21 level in patients with T2D, particularly in those with better glucose control.Interpretation: We identify that function of GLP-1 in inhibiting hepatic glucose output is mediated via the liver hormone FGF21. Thus, we provide a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis. (c) 2019 The Authors. Published by Elsevier B.V.