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JCI:山东大学于晓和龚瑶琴教授课题组发表糖尿病相关研究论文

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摘要 : 2017年6月12日,国际医学领域经典权威期刊《The Journal of Clinical Investigation》山东大学基础医学院生理与病理生理学系于晓教授课题组和遗传学系龚瑶琴教授课题组的共同研究成果

2017年6月12日,国际医学领域经典权威期刊《The JouRNAl of Clinical Investigation》山东大学基础医学院生理与病理生理学系于晓教授课题组和遗传学系龚瑶琴教授课题组的共同研究成果,研究论文题为“A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions ”(“Cullin 4B-RING E3泛素连接酶复合物精细调控胰岛δ细胞旁分泌作用”。生理与病理生理学系博士研究生李青、杨帆及生理与病理生理学系崔敏副教授为本文并列第一作者,于晓教授与龚瑶琴教授为共同通讯作者。

糖尿病是以血糖紊乱为特征的影响人类健康的重大疾病。作为调节血糖的重要组织,胰岛稳态的维持非常重要;而破坏胰岛稳态很容易导致糖尿病。胰岛稳态由胰岛中的α、β、δ、pp和ε细胞间的细胞环路精细调节,但其相关机制目前还缺乏了解。

于晓教授课题组一直致力于胰岛环路研究,已经阐明了肾上腺素能受体和GPCR信号通路对胰岛稳态的调节作用(《Diabetologia》,2014;2015)。龚瑶琴教授课题组近十年来在泛素连接酶复合物骨架蛋白CUL4B功能研究方面取得了系列成果(《AJHG》,2007;《Cancer Cell》,2012;《JCB》,2013;《Cancer Res》,2015;《Diabetes》,2017)。最近,于晓教授课题组和龚瑶琴教授课题组联合研究发现,长时程的高血糖或者旁分泌因子UCN3通过调控CUL4B和EZH2的表达,改变胰岛中的核心枢纽δ细胞的表观遗传学状态,从而引起L型钙通道Cav1.2和腺苷酸环化酶AC6的表达变化,最终在胰岛稳态和血糖调节中发挥重要作用;而胰岛δ细胞特异性敲除CUL4B的小鼠胰岛生长抑素分泌增加,进而通过旁分泌作用使胰岛素分泌下降,最终引起葡萄糖不耐受;同时,在人的胰岛δ细胞中,也验证了CUL4B表达下调或活力降低促进生长抑素的分泌。该研究第一次揭示了胰岛的调控“司令官”δ细胞被生理刺激后在表观遗传的水平上是如何被调控,从而适应外界环境的刺激,并做出相应的反应。该研究对理解胰岛稳态与血糖稳态的维持过程具有重要的生理和病理生理意义。

JCI:山东大学于晓和龚瑶琴教授课题组发表糖尿病相关研究论文
原文链接:

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ Cell paracrine interactions

原文摘要:

Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in δ cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies showed that the CRL4B-PRC2 complex, under the control of the δ cell–specific transcription factor hematopoietically expressed homeobox (HHEX), determines the levels of intracellular calcium and cAMP through histone posttranslational modifications, thereby altering expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin 3 (UCN3) stimulation, increased expression of cullin 4B (CUL4B) and the PRC2 subunit histone-lysine N-methyltransferase EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of δ cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.

doi:10.1172/JCI91348

作者:于晓和龚瑶琴 点击:

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