Publication Date:
2019
Description:
〈p〉Publication date: 1 October 2019〈/p〉
〈p〉〈b〉Source:〈/b〉 Biochemical and Biophysical Research Communications, Volume 517, Issue 4〈/p〉
〈p〉Author(s): Pengzhou Li, Xiang Gao, Xulong Sun, Weizheng Li, Bo Yi, Liyong Zhu〈/p〉
〈div xml:lang="en"〉
〈h5〉Abstract〈/h5〉
〈div〉〈p〉Type II diabetes is a complex, chronic, and progressive disease. Previously, we demonstrate that FXR inhibits GLP-1 secretion via interacting with CREB to inhibit the transcriptional activity of CREB, thus promoting the development of type II diabetes. Epigenetic modifications, such as DNA methylation, histone acetylation, and post-transcriptional RNA regulation, are essential mediators contributing to diabetes-associated morbidity and mortality. Thus, we attempted to investigate the epigenetic mechanisms of FXR modulating GLP-1 secretion. Firstly, the involvement of histone acetylation, DNA methylation, and post-transcriptional regulation in FXR inhibiting GLP-1 secretion was verified. As FXR overexpression significantly inhibited the activity of GCG 3′-UTR, we hypothesize that miRNA might participate in the mechanism. Two online tools and real-time PCR revealed that FXR promoted miR-33 expression. Moreover, miR-33 inhibited the expression of GCG and CREB1 through direct targeting in STC-1 cells. FXR overexpression in STC-1 cells significantly reduced the mRNA expression and protein levels of both GCG and CREB1, as well as the secretion of GLP-1; miR-33 inhibition exerted opposing effects. More importantly, the effects of FXR overexpression were significantly reversed by miR-33 inhibition, indicating that FXR inhibited GLP-1 secretion through promoting miR-33 expression, therefore inhibiting the expression of miR-33 targets, GCG and CREB1. In conclusion, we provide a novel epigenetic mechanism by which FXR inhibits the secretion of GLP-1 through miR-33 and its two downstream targets, GCG and CREB1. These findings might provide innovative strategies for improving type II diabetes, which needs further 〈em〉in vivo〈/em〉 and clinical investigation.〈/p〉〈/div〉
〈/div〉
Print ISSN:
0006-291X
Electronic ISSN:
1090-2104
Topics:
Biology
,
Chemistry and Pharmacology
,
Physics
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