FXR Mediates Adenylyl Cyclase 8 Expression in Pancreatic β-Cells
FXR Mediates Adenylyl Cyclase 8 Expression in Pancreatic β-Cells
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FXR 介导胰腺 β 细胞中腺苷酸环化酶 8 的表达
DOI：
10.1155/2019/8915818
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发表时间：
2019-08-14
影响因子：
4.3
通讯作者：
Ma, Xiaosong
中科院分区：
文献类型：
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作者：
Kong, Xiangchen;Li, Bingfeng;Ma, Xiaosong
腺苷酸环化酶8（ADCY 8）和法尼醇X受体（FXR）已在胰腺β细胞中被鉴定，并且在胰岛素分泌中起重要作用。但是，β细胞中ADCY 8表达调控的潜在机制，特别是FXR是否参与其中，仍然未被探索。我们现在表明，ADCY 8的表达减少Goto-Kaldzald（GK）大鼠胰岛相比，健康的Wistar对照。我们还发现ADCY 8的减少与FXR表达的减少有关。因此，在INS-1 832/13细胞以及来自FXR敲除小鼠的胰岛中，ADCY 8表达被FXR敲除抑制。相反，ADCY 8表达在FXR过表达的INS-1 832/13细胞中或在FXR活化的情况下增加。在机制上，FXR直接结合Adcy 8启动子并募集组蛋白乙酰转移酶类固醇受体辅激活因子1（SRC 1），从而导致Adcy 8基因座中组蛋白H3的乙酰化增加，促进β细胞中Adcy 8基因的转录。因此，这项研究表明，FXR是一个关键的转录因子，介导的ADCY 8在胰腺β细胞的表达，并表征了与Adcy 8转录相关的染色质修饰。
Adenylyl cyclase 8 (ADCY8) and Farnesoid X Receptor (FXR) have been identified in pancreatic beta-cells and play important roles in insulin secretion. But the mechanisms underlying with respect to the regulation of ADCY8 expression in beta-cells, particularly whether FXR is involved, remain unexplored. We now show that ADCY8 expression is decreased in Goto-Kaldzald (GK) rat islets compared with healthy Wistar controls. We also found that reduced ADCY8 is associated with decreased expression of FXR. Consistently, ADCY8 expression was suppressed by the knockdown of FXR in INS-1 832/13 cells, as well as the islets from FXR knockout mice. On the contrary, ADCY8 expression was increased in FXR-overexpressed INS-1 832/13 cells or in the case of FXR activation. Mechanistically, FXR directly binds to Adcy8 promoter and recruits the histone acetyltransferase Steroid Receptor Coactivator 1 (SRC1), thereby resulting in the increased acetylation of histone H3 in Adcy8 locus, promoting Adcy8 gene transcription in beta-cells. Thus, this study indicates that FXR is a critical transcription factor that mediates ADCY8 expression in pancreatic beta-cells and has characterized the chromatin modification associated with Adcy8 transcription.