A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions
Qing Li ... Yaoqin Gong, Xiao Yu
Qing Li ... Yaoqin Gong, Xiao Yu
Published June 30, 2017
Citation Information: J Clin Invest. 2017;127(7):2631-2646. doi:10.1172/JCI91348.
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Categories: Research Article Endocrinology Metabolism

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

Abstract

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.

Authors

Qing Li, Min Cui, Fan Yang, Na Li, Baichun Jiang, Zhen Yu, Daolai Zhang, Yijing Wang, Xibin Zhu, Huili Hu, Pei-Shan Li, Shang-Lei Ning, Si Wang, Haibo Qi, Hechen Song, Dongfang He, Amy Lin, Jingjing Zhang, Feng Liu, Jiajun Zhao, Ling Gao, Fan Yi, Tian Xue, Jin-Peng Sun, Yaoqin Gong, Xiao Yu

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CUL4B deficiency in pancreatic δ cells impairs glucose metabolism. (A an...

Figure 1

CUL4B deficiency in pancreatic δ cells impairs glucose metabolism.

(A and B) Western blots and quantitative data for CUL4A and CUL4B protein levels in islets from 12-week-old diabetic db/db mice and their heterozygous littermates (db/+). n = 6 mice per group. Representative Western blots from at least 3 independent experiments are shown. (C) Immunostaining for CUL4B (green) and somatostatin (SST, red) in pancreatic sections from db/db and db/+ mice. Scale bar: 100 μm. n = 6 mice per group; 4–7 random areas were selected from each islet section, and 10 sections were randomly selected from each mouse. (D) Confirmation of pancreatic δ cell–specific CUL4B deficiency (Sst-Cre+/– Cul4bfl/Y) through immunofluorescence. The colocalization of somatostatin (red) and CUL4B (green) in δ cells of WT mice was absent in Sst-Cre+/– Cul4bfl/Y mice. Scale bar: 100 μm. (E) Immunostaining for insulin (red) and somatostatin (green) in WT and Sst-Cre+/– Cul4bfl/Y mice. Scale bar: 50 μm. (F) Quantitative data for islet density, pancreatic δ cell number, and β cell mass. n = 6 mice per group; 4–10 random areas were selected from each section, and 12 sections were randomly selected from each mouse. (G) The fasting and fed blood glucose levels of Sst-Cre+/– Cul4bfl/Y mice and their WT littermates. n = 8 mice per group. (H) Glucose tolerance test for Sst-Cre+/– Cul4bfl/Y mice and their WT littermates (n = 11–12). (I) Insulin tolerance test for Sst-Cre+/– Cul4bfl/Y mice and their WT littermates. Insulin-induced decreases in blood glucose levels were significantly lower in Sst-Cre+/– Cul4bfl/Y mice than in their WT littermates, and they did not return to baseline levels at the 2-hour time point, whereas the levels of their WT littermates did (n = 9–11). *P < 0.05; **P < 0.01; ***P < 0.001. db/db mice were compared with their db/+ littermates, and Sst-Cre+/– Cul4bfl/Y mice were compared with their WT littermates. Error bars in F represent mean ± SD; other bars represent mean ± SEM. All data were analyzed using 1-way ANOVA.