Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets
Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets
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DOI：
10.1210/en.2004-1119
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发表时间：
2005-01-01
期刊：
影响因子：
4.8
通讯作者：
Holst, JJ
中科院分区：
文献类型：
--
作者：
Burrin, DG;Stoll, B;Holst, JJ
胰高血糖素样肽2（GLP-2）是一种肠道激素，可刺激全胃肠外营养（TPN）喂养仔猪的粘膜生长;然而，对细胞凋亡、细胞增殖和蛋白质合成的剂量依赖性影响尚不清楚。我们研究了38头TPN喂养的新生仔猪，以三种速率（2.5、5.0和10.0 nmol . kg（-1）。d（-1））为7 d。低输注组和高输注组的血浆GLP-2浓度范围分别为177 +/- 27至692 +/- 85 pM。GLP-2输注剂量依赖性地增加小肠重量、DNA和蛋白质含量以及绒毛高度;然而，GLP-2降低胃蛋白质合成。肠隐窝和绒毛细胞凋亡减少，隐窝细胞数量与GLP-2输注速率呈线性增加，而细胞增殖和蛋白质合成仅在高GLP-2剂量下刺激。随着输注速率和GLP-2血浆浓度的增加，肠内caspase-3和-6的活性以及活性caspase-3的丰度下降，而procaspase-3的丰度显着增加。GLP-2对肠细胞凋亡和caspase-3活性的剂量依赖性抑制与蛋白激酶B和糖原合成酶激酶-3磷酸化增加相关，但磷脂酰肌醇3-激酶的表达不受GLP-2的影响。肠内皮型一氧化氮合酶mRNA和蛋白表达增加，但仅在高GLP-2剂量。我们的结论是，刺激肠上皮细胞的生存是浓度依赖性的GLP-2生理浓度，但是，诱导细胞增殖和蛋白质合成是一种药理学反应。此外，我们发现GLP-2刺激肠细胞的存活和增殖与诱导蛋白激酶B和糖原合成酶激酶-3磷酸化和Bcl-2表达有关。
Glucagon-like peptide 2 (GLP-2) is a gut hormone that stimulates mucosal growth in total parenteral nutrition (TPN)-fed piglets; however, the dose-dependent effects on apoptosis, cell proliferation, and protein synthesis are unknown. We studied 38 TPN-fed neonatal piglets infused iv with either saline or GLP-2 at three rates (2.5, 5.0, and 10.0 nmol . kg(-1) . d(-1)) for 7 d. Plasma GLP-2 concentrations ranged from 177 +/- 27 to 692 +/- 85 pM in the low- and high-infusion groups, respectively. GLP-2 infusion dose-dependently increased small intestinal weight, DNA and protein content, and villus height; however, stomach protein synthesis was decreased by GLP-2. Intestinal crypt and villus apoptosis decreased and crypt cell number increased linearly with GLP-2 infusion rates, whereas cell proliferation and protein synthesis were stimulated only at the high GLP-2 dose. The intestinal activities of caspase-3 and -6 and active caspase-3 abundance decreased, yet procaspase-3 abundance increased markedly with increasing infusion rate and plasma concentration of GLP-2. The GLP-2-dose-dependent suppression of intestinal apoptosis and caspase-3 activity was associated with increased protein kinase B and glycogen-synthase kinase-3 phosphorylation, yet the expression phosphatidylinositol 3-kinase was unaffected by GLP-2. Intestinal endothelial nitric oxide synthase mRNA and protein expression was increased, but only at the high GLP-2 dose. We conclude that the stimulation of intestinal epithelial survival is concentration dependent at physiological GLP-2 concentrations; however, induction of cell proliferation and protein synthesis is a pharmacological response. Moreover, we show that GLP-2 stimulates intestinal cell survival and proliferation in association with induction of protein kinase B and glycogensynthase kinase-3 phosphorylation and Bcl-2 expression.