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Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production
BACKGROUND: Pancreatic fibrosis is a pathophysiological process associated with excessive deposition of extracellular matrix in pancreas, leading to reduced insulin secretion and derangement of glucose metabolism. X/A-like cells, a group of unique endocrine cells in gastric oxyntic mucosa, produce a...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197745/ https://www.ncbi.nlm.nih.gov/pubmed/30266297 http://dx.doi.org/10.1016/j.ebiom.2018.09.027 |
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author | Yu, Ruili Li, Ziru Liu, Shiying Huwatibieke, Bahetiyaer Li, Yin Yin, Yue Zhang, Weizhen |
author_facet | Yu, Ruili Li, Ziru Liu, Shiying Huwatibieke, Bahetiyaer Li, Yin Yin, Yue Zhang, Weizhen |
author_sort | Yu, Ruili |
collection | PubMed |
description | BACKGROUND: Pancreatic fibrosis is a pathophysiological process associated with excessive deposition of extracellular matrix in pancreas, leading to reduced insulin secretion and derangement of glucose metabolism. X/A-like cells, a group of unique endocrine cells in gastric oxyntic mucosa, produce and secret ghrelin to influence energy balance. Whether gastric X/A-like cells affect pancreatic fibrosis and subsequent glucose homeostasis remains unclear. METHODS: We established a Ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of ghrelin-promoter. TSC1(flox/flox) mice were bred with Ghrl-cre mice to generate Ghrl-TSC1−/− (TG) mice, within which mTORC1 signaling was activated in X/A-like cells. Pancreatic fibrosis and insulin secretion were analyzed in the TG mice. FINDINGS: Activation of mTORC1 signaling by deletion of TSC1 gene in gastric X/A-like cells induced spontaneous pancreatic fibrosis. This alteration was associated with reduced insulin expression and secretion, as well as impaired glucose metabolism. Activation of mTORC1 signaling in gastric X/A-like cells reduced gastric and circulating ghrelin levels. Exogenous ghrelin reversed pancreatic fibrosis and glucose intolerance induced by activation of mTORC1 signaling in these cells. Rapamycin, an inhibitor of mTOR, reversed the decrease of ghrelin levels and pancreatic fibrosis. INTERPRETATION: Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and subsequently impairs glucose homeostasis via suppression of ghrelin. |
format | Online Article Text |
id | pubmed-6197745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-61977452018-10-24 Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production Yu, Ruili Li, Ziru Liu, Shiying Huwatibieke, Bahetiyaer Li, Yin Yin, Yue Zhang, Weizhen EBioMedicine Research paper BACKGROUND: Pancreatic fibrosis is a pathophysiological process associated with excessive deposition of extracellular matrix in pancreas, leading to reduced insulin secretion and derangement of glucose metabolism. X/A-like cells, a group of unique endocrine cells in gastric oxyntic mucosa, produce and secret ghrelin to influence energy balance. Whether gastric X/A-like cells affect pancreatic fibrosis and subsequent glucose homeostasis remains unclear. METHODS: We established a Ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of ghrelin-promoter. TSC1(flox/flox) mice were bred with Ghrl-cre mice to generate Ghrl-TSC1−/− (TG) mice, within which mTORC1 signaling was activated in X/A-like cells. Pancreatic fibrosis and insulin secretion were analyzed in the TG mice. FINDINGS: Activation of mTORC1 signaling by deletion of TSC1 gene in gastric X/A-like cells induced spontaneous pancreatic fibrosis. This alteration was associated with reduced insulin expression and secretion, as well as impaired glucose metabolism. Activation of mTORC1 signaling in gastric X/A-like cells reduced gastric and circulating ghrelin levels. Exogenous ghrelin reversed pancreatic fibrosis and glucose intolerance induced by activation of mTORC1 signaling in these cells. Rapamycin, an inhibitor of mTOR, reversed the decrease of ghrelin levels and pancreatic fibrosis. INTERPRETATION: Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and subsequently impairs glucose homeostasis via suppression of ghrelin. Elsevier 2018-09-25 /pmc/articles/PMC6197745/ /pubmed/30266297 http://dx.doi.org/10.1016/j.ebiom.2018.09.027 Text en © 2018 Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Yu, Ruili Li, Ziru Liu, Shiying Huwatibieke, Bahetiyaer Li, Yin Yin, Yue Zhang, Weizhen Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production |
title | Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production |
title_full | Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production |
title_fullStr | Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production |
title_full_unstemmed | Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production |
title_short | Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production |
title_sort | activation of mtorc1 signaling in gastric x/a-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197745/ https://www.ncbi.nlm.nih.gov/pubmed/30266297 http://dx.doi.org/10.1016/j.ebiom.2018.09.027 |
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