Cargando…
FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by glucose metabolic disorders, and gluconeogenesis inhibiting is a promisingly therapeutic strategy for T2DM. Glucocorticoid receptor (GR) is tightly implicated in the regulation of gluconeogenesis, although the underlying...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880398/ https://www.ncbi.nlm.nih.gov/pubmed/33316780 http://dx.doi.org/10.18632/aging.202275 |
_version_ | 1783650696582660096 |
---|---|
author | Xu, Xin Chen, Yidi Zhu, Danyang Zhao, Tong Xu, Rui Wang, Jiaying Hu, Lihong Shen, Xu |
author_facet | Xu, Xin Chen, Yidi Zhu, Danyang Zhao, Tong Xu, Rui Wang, Jiaying Hu, Lihong Shen, Xu |
author_sort | Xu, Xin |
collection | PubMed |
description | Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by glucose metabolic disorders, and gluconeogenesis inhibiting is a promisingly therapeutic strategy for T2DM. Glucocorticoid receptor (GR) is tightly implicated in the regulation of gluconeogenesis, although the underlying mechanism remains obscure. Here, we discovered that small molecule, 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide (FX5) as a new non-steroidal GR antagonist efficiently ameliorated glucose homeostasis in db/db and HFD/STZ-induced T2DM mice. The mechanism underlying the suppression of FX5 against gluconeogenesis was highly investigated. FX5 suppressed gluconeogenetic genes G6Pase and PEPCK in mouse primary hepatocytes and liver tissues of T2DM mice. Results of mammalian one-hybrid and transactivation as well as nuclear translocation assays totally evaluated the antagonistic features of FX5 against GR. Moreover, siRNA and overexpression related assays verified that FX5 alleviated gluconeogenesis either directly by antagonizing GR or indirectly through GR/HNF4α/miR122-5p signaling pathway. Our work has presented a new mode for GR antagonist in the regulation of gluconeogenesis, which is expected to highlight the potential of FX5 in the treatment of T2DM. |
format | Online Article Text |
id | pubmed-7880398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-78803982021-02-22 FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway Xu, Xin Chen, Yidi Zhu, Danyang Zhao, Tong Xu, Rui Wang, Jiaying Hu, Lihong Shen, Xu Aging (Albany NY) Research Paper Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by glucose metabolic disorders, and gluconeogenesis inhibiting is a promisingly therapeutic strategy for T2DM. Glucocorticoid receptor (GR) is tightly implicated in the regulation of gluconeogenesis, although the underlying mechanism remains obscure. Here, we discovered that small molecule, 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide (FX5) as a new non-steroidal GR antagonist efficiently ameliorated glucose homeostasis in db/db and HFD/STZ-induced T2DM mice. The mechanism underlying the suppression of FX5 against gluconeogenesis was highly investigated. FX5 suppressed gluconeogenetic genes G6Pase and PEPCK in mouse primary hepatocytes and liver tissues of T2DM mice. Results of mammalian one-hybrid and transactivation as well as nuclear translocation assays totally evaluated the antagonistic features of FX5 against GR. Moreover, siRNA and overexpression related assays verified that FX5 alleviated gluconeogenesis either directly by antagonizing GR or indirectly through GR/HNF4α/miR122-5p signaling pathway. Our work has presented a new mode for GR antagonist in the regulation of gluconeogenesis, which is expected to highlight the potential of FX5 in the treatment of T2DM. Impact Journals 2020-12-09 /pmc/articles/PMC7880398/ /pubmed/33316780 http://dx.doi.org/10.18632/aging.202275 Text en Copyright: © 2021 Xu et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Xu, Xin Chen, Yidi Zhu, Danyang Zhao, Tong Xu, Rui Wang, Jiaying Hu, Lihong Shen, Xu FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway |
title | FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway |
title_full | FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway |
title_fullStr | FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway |
title_full_unstemmed | FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway |
title_short | FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway |
title_sort | fx5 as a non-steroidal gr antagonist improved glucose homeostasis in type 2 diabetic mice via gr/hnf4α/mir-122-5p pathway |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880398/ https://www.ncbi.nlm.nih.gov/pubmed/33316780 http://dx.doi.org/10.18632/aging.202275 |
work_keys_str_mv | AT xuxin fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway AT chenyidi fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway AT zhudanyang fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway AT zhaotong fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway AT xurui fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway AT wangjiaying fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway AT hulihong fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway AT shenxu fx5asanonsteroidalgrantagonistimprovedglucosehomeostasisintype2diabeticmiceviagrhnf4amir1225ppathway |