Glucagon-like peptide-1 receptor expression and its functions are regulated by androgen.
Glucagon-like peptide-1 receptor expression and its functions are regulated by androgen.
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DOI：
10.1016/j.biopha.2019.109555
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发表时间：
2019-12
期刊：
影响因子：
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通讯作者：
Liying Zhu;Jinxin Zhou;Yu Pan;J. Lv;Yang Liu;Shanhe Yu;Yifan Zhang
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作者：
Liying Zhu;Jinxin Zhou;Yu Pan;J. Lv;Yang Liu;Shanhe Yu;Yifan Zhang
胰高血糖素样肽-1受体（GLP-1 R）是2型糖尿病的重要药理学靶点，它能维持血糖稳态并促进β细胞增殖。雄激素不仅调节下丘脑-垂体-性腺轴，而且影响代谢。Glp 1 rmRNA在正常雄性小鼠中广泛表达，其表达水平与血清睾酮（T）浓度呈正相关。利用高表达GLP-1 R的小鼠胰岛素瘤6（MIN 6）细胞，我们观察到双氢睾酮（DHT）诱导GLP-1 R在转录和蛋白水平上上调，而雄激素受体抑制剂ARN-509或靶向Glp 1 rmRNA的小干扰RNA（siRNA）则下调GLP-1 R。在正常C57 BL/6小鼠和db/db小鼠中，在DHT治疗组中胰腺中Glp 1 rmRNA水平增加，而在ARN-509治疗组中降低。GLP-1 R表达增加在体外和体内均具有促胰岛素分泌功能。进一步分析发现，雄激素受体（Ar）定位于MIN 6细胞的胞浆中，并在DHT处理后易位到细胞核中。此外，我们还发现Glp 1 r基因的启动子区存在一个Ar基序。进一步的研究表明，从胞质到细胞核的DHT/Ar复合物与Glp 1 r基因的Ar基序结合，并上调基因转录。总之，在生理条件下和糖尿病模型中，广泛表达的GLP-1 R在转录水平上受到雄激素的正调控。
Glucagon-like peptide-1 receptor (GLP-1R) is an important pharmacological target for type 2 diabetes mellitus because it maintains glucose homeostasis and promotes β cell proliferation. Androgen is suggested not only to regulate hypothalamic-pituitary-gonadal axis but also to affect metabolism. In this study,Glp1rmRNA was found widely expressed in normal male mice and its levels were positively correlated with the serum testosterone (T) concentrations. Using mouse insulinoma 6 (MIN6) cells, which highly express GLP-1R, we observed GLP-1R was upregulated both at transcriptional and protein levels induced by dihydrotestosterone (DHT) and was downregulated by androgen receptor inhibitor ARN-509 or small interfering RNA (siRNA) targetingGlp1rmRNA. In normal C57BL/6 mice and db/db mice,Glp1rmRNA levels in the pancreases increased in the DHT treatment group and decreased in the ARN-509 treatment group. And the increased GLP-1R expression had insulinotropic function bothin vitroandin vivo. Further analysis showed that the androgen receptor (Ar) located in the cytosol of MIN6 cells and translocated to the nucleus after DHT treatment. In addition, we found that there was an Ar motif in the promoter region of theGlp1rgene. Further studies revealed that the translocated DHT/Ar complex from the cytosol to the nucleus bound to the Ar motif of theGlp1rgene and upregulated gene transcription. Taken together, the widely expressed GLP-1R was positively regulated by androgen under physiological condition and in diabetic models at the transcriptional level.