Exendin-4 regulates pancreatic ABCA1 transcription via CaMKK/CaMKIV pathway.
Exendin-4 regulates pancreatic ABCA1 transcription via CaMKK/CaMKIV pathway.
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DOI：
10.1111/j.1582-4934.2009.00955.x
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发表时间：
2010-05
影响因子：
5.3
通讯作者：
Tokumitsu H
中科院分区：
文献类型：
--
作者：
Li J;Murao K;Imachi H;Masugata H;Iwama H;Tada S;Zhang GX;Kobayashi R;Ishida T;Tokumitsu H
胰岛β细胞中atp结合盒转运蛋白A1 （ABCA1）影响胰岛素分泌和葡萄糖稳态。本研究探讨了胰高血糖素样肽1的长效激动剂，即exendin-4，其介导对ABCA1基因表达的刺激作用，是否会干扰Ca2+/钙调蛋白（CaM）依赖性蛋白激酶（CaMK）级联反应。用报告基因法检测大鼠胰岛素分泌INS-1细胞中ABCA1启动子活性。通过检测CaMKIV的激活环磷酸化（Thr196）来评估CaMKIV的活性。我们研究了组成活性形式（CaMKIVc）或CaMKIV敲低对ABCA1表达的影响。随着exendin-4浓度的增加，ABCA1蛋白的丰度增加，在10 nM处诱导最大。Exendin-4也刺激ABCA1启动子活性，但在CaMKK抑制剂STO-609存在时不起作用。CaMKIV磷酸化上调（Thr196）在暴露于exendin-4 10分钟后达到峰值。CaMKIVc增强或上调INS-1细胞中ABCA1启动子活性。此外，在CaMKIV-siRNA处理的细胞中，exendin-4诱导的ABCA1蛋白表达被显著抑制。exendin-4激活CaMKK/CaMKIV级联可刺激ABCA1基因转录，表明exendin-4在胰腺β细胞胰岛素分泌和胆固醇酯含量中起重要作用。
ATP-binding cassette transporter A1 (ABCA1) in pancreatic β cells influences insulin secretion and glucose homeostasis. This study investigates whether the long-acting agonist of the glucagon-like peptide 1, namely exendin-4, which mediates stimulatory effects on ABCA1 gene expression, could interfere with the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) cascade. ABCA1 promoter activity was examined by reporter gene assay in rat insulin-secreting INS-1 cells incubated with exendin-4. CaMKIV activity was assessed by detection of activation-loop phosphorylation (Thr196) of CaMKIV. We investigated the influence of the constitutively active form (CaMKIVc) or CaMKIV knockdown on ABCA1 expression. Increased abundance of ABCA1 protein was noted in response to rising concentrations of exendin-4 with maximum induction at 10 nM. Exendin-4 also stimulated ABCA1 promoter activity, but failed to do so in the presence of STO-609, a CaMKK inhibitor. Up-regulation of CaMKIV phosphorylation (at Thr196) peaked after 10 min. of exposure to exendin-4. CaMKIVc enhanced or up-regulated ABCA1 promoter activity in INS-1 cells. Furthermore, exendin-4 induction of ABCA1 protein expression was significantly suppressed in cells treated with CaMKIV-siRNA. Activation of the CaMKK/CaMKIV cascade by exendin-4 stimulated ABCA1 gene transcription, indicating that exendin-4 plays an important role in insulin secretion and cholesterol ester content in pancreatic β cells.
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影响因子：
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Brunham, Liam R.;Kruit, Janine K.;Hayden, Michael R.
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