Glucocorticoids decrease the production of glucagon-like peptide-1 at the transcriptional level in intestinal L-cells
Glucocorticoids decrease the production of glucagon-like peptide-1 at the transcriptional level in intestinal L-cells
复制标题
糖皮质激素在肠道 L 细胞转录水平上减少胰高血糖素样肽-1 的产生
DOI：
10.1016/j.mce.2015.02.014
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发表时间：
2015
影响因子：
4.1
通讯作者：
Noriyasu Hirasawa
中科院分区：
文献类型：
--
作者：
Taiki Sato;Hiroto Hayashi;Masahiro Hiratsuka;Noriyasu Hirasawa
糖皮质激素被广泛用作抗炎或免疫抑制药物，但其副作用常引起高血糖。胰高血糖素样肽-1 （Glucagon-like peptide-1, GLP-1）由肠L细胞分泌，在维持葡萄糖稳态中起重要作用。然而，糖皮质激素对L细胞GLP-1产生途径的直接影响尚不清楚。我们研究了糖皮质激素对体外和体内GLP-1生成的影响。在L细胞系中，糖皮质激素在蛋白和mRNA水平上降低GLP-1的释放和前体胰高血糖素的表达，而米非司酮则抑制了这一作用。小鼠给药地塞米松或布地奈德显著降低回肠胰高血糖素原mRNA表达，部分降低葡萄糖刺激的GLP-1分泌。化合物A，解离糖皮质激素受体调节剂，不影响胰高血糖素原的体外表达。这些结果表明糖皮质激素通过糖皮质激素受体二聚化依赖机制在L细胞的转录水平上直接降低GLP-1的产生。
Glucocorticoids are widely used as anti-inflammatory or immunosuppressive drugs, but often induce hyperglycemia as a side effect. Glucagon-like peptide-1 (GLP-1) is secreted from intestinal L cells and plays crucial roles in maintaining glucose homeostasis. However, the direct effects of glucocorticoids on the GLP-1 production pathway in L cells remain unclear. We investigated the effects of glucocorticoids on GLP-1 productionin vitroandin vivo. In L cell lines, glucocorticoids decreased GLP-1 release and expression of the precursor, proglucagon, at protein and mRNA levels, which were inhibited by mifepristone. The administration of dexamethasone or budesonide to mice significantly decreased the mRNA expression of proglucagon in the ileum and partially decreased glucose-stimulated GLP-1 secretion. Compound A, a dissociated glucocorticoid receptor modulator, did not affect the expression of proglucagonin vitro. These results suggested that glucocorticoids directly reduced GLP-1 production at the transcriptional level in L cells through a glucocorticoid receptor dimerization-dependent mechanism.