Activation of MTORC1 Signaling in Gastric X/A-like Cells Induces Spontaneous Pancreatic Fibrosis and Derangement of Glucose Metabolism by Reducing Ghrelin Production

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2018 Sep 30

PMID 30266297

Citations 9

Authors

Ruili Yu

Ziru Li

Shiying Liu

Bahetiyaer Huwatibieke

Yin Li

Yue Yin

Weizhen Zhang

Affiliations

Soon will be listed here.

Abstract

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 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.

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