Abstract
Intestinal absorption and barrier malfunctions are associated with endoplasmic reticulum stress (ERS) in the intestine. We induced ERS by exposing the intestinal porcine epithelial cell line J2 (IPEC-J2) to tunicamycin (TUNI) to explore the potential of l-glutamine to reduce ERS-induced apoptosis. Our experiments demonstrated that exposing cells to TUNI results in spontaneous ERS and encourages the upregulation of glucose-regulated protein 78 (GRP78). Prolonged TUNI-induced ERS was found to increase apoptosis mediated by C/enhancer binding protein homologous protein (CHOP), accompanied by GRP78 downregulation. Treatment with l-glutamine was found to promote cell proliferation within the growth medium but to have little effect in basic Dulbecco’s modified Eagle medium. Finally, in the milieu of TUNI-induced ERS, l-glutamine was found to maintain a high level of GRP78, alleviate CHOP-mediated apoptosis and activate the inositol requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis. A specific inhibitor of the IRE1α-XBP1 axis reversed the protective effect of l-glutamine by blocking the expression of IRE1α/XBP1s. We propose that the functional effect of l-glutamine on intestinal health may be partly due to its modulation of ERS and CHOP-mediated apoptosis.
Highlights
The amino acid L-glutamine is considered to be the carbon source for purine and pyrimidine synthesis
The unfolded protein response (UPR) pathway is regularly triggered by endoplasmic reticulum stress (ERS) in the intestinal epithelium, and several reports have suggested that inflammatory bowel disease is involved in the induction of ERS
TUNI was found to encourage the upregulation of glucose-regulated protein 78 (GRP78) (Figure 1D,F) and increase the expression of GADD153/C/enhancer binding protein homologous protein (CHOP) (Figure 1C) and cleaved caspase-3 (Figure 1E), indicating that spontaneous ERS and ERS-mediated cell apoptosis had been triggered in this cell model
Summary
The amino acid L-glutamine is considered to be the carbon source for purine and pyrimidine synthesis. It participates in the Coriolis cycle through deamination and related procedures [1], and becomes essential when the body suffers from metabolic stresses such as trauma [2], cancer [3], sepsis [4], or burns [5]. L-glutamine deficiency disturbs amino acid metabolism in intestinal epithelial cells [7], attenuates their mammalian target of rapamycin (mTOR) pathway [8] and downregulates mitogen-activated protein kinase/extracellular signal-regulated kinase signalling, thereby inhibiting protein synthesis and cell proliferation [9]
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