Regulation of Intestinal Epithelial Cells Properties and Functions by Amino Acids

Intestinal epithelial cells (IECs) line the surface of intestinal epithelium, where they play important roles in the digestion of food, absorption of nutrients, and protection of the human body from microbial infections, and others. Dysfunction of IECs can cause diseases. The development, maintenance, and functions of IECs are strongly influenced by external nutrition, such as amino acids. Amino acids play important roles in regulating the properties and functions of IECs. In this article, we briefly reviewed the current understanding of the roles of amino acids in the regulation of IECs’ properties and functions in physiological state, including in IECs homeostasis (differentiation, proliferation, and renewal), in intestinal epithelial barrier structure and functions, and in immune responses. We also summarized some important findings on the effects of amino acids supplementation (e.g., glutamine and arginine) in restoring IECs’ and intestine functions in some diseased states. These findings will further our understanding of the important roles of amino acids in the homeostasis of IECs and could potentially help identify novel targets and reagents for the therapeutic interventions of diseases associated with dysfunctional IECs.

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JunD Represses Transcription and Translation of the Tight Junction Protein Zona Occludens-1 Modulating Intestinal Epithelial Barrier Function

Molecular Biology of the Cell ◽

10.1091/mbc.e08-02-0175 ◽

2008 ◽

Vol 19 (9) ◽

pp. 3701-3712 ◽

Cited By ~ 45

Author(s):

Jie Chen ◽

Lan Xiao ◽

Jaladanki N. Rao ◽

Tongtong Zou ◽

Lan Liu ◽

...

Keyword(s):

Epithelial Cells ◽

Tight Junction ◽

Barrier Function ◽

Intestinal Epithelial Cells ◽

Binding Protein ◽

Mrna Translation ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function

The AP-1 transcription factor JunD is highly expressed in intestinal epithelial cells, but its exact role in maintaining the integrity of intestinal epithelial barrier remains unknown. The tight junction (TJ) protein zonula occludens (ZO)-1 links the intracellular domain of TJ-transmembrane proteins occludin, claudins, and junctional adhesion molecules to many cytoplasmic proteins and the actin cytoskeleton and is crucial for assembly of the TJ complex. Here, we show that JunD negatively regulates expression of ZO-1 and is implicated in the regulation of intestinal epithelial barrier function. Increased JunD levels by ectopic overexpression of the junD gene or by depleting cellular polyamines repressed ZO-1 expression and increased epithelial paracellular permeability. JunD regulated ZO-1 expression at the levels of transcription and translation. Transcriptional repression of ZO-1 by JunD was mediated through cAMP response element-binding protein-binding site within its proximal region of the ZO-1-promoter, whereas induced JunD inhibited ZO-1 mRNA translation by enhancing the interaction of the ZO-1 3′-untranslated region with RNA-binding protein T cell-restricted intracellular antigen 1-related protein. These results indicate that JunD is a biological suppressor of ZO-1 expression in intestinal epithelial cells and plays a critical role in maintaining epithelial barrier function.

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A basis for the difference in the inhibition of the uptake of various neutral amino acids by lysine in intestinal epithelial cells

Biochimica et Biophysica Acta (BBA) - Biomembranes ◽

10.1016/0005-2736(72)90136-8 ◽

1972 ◽

Vol 266 (1) ◽

pp. 217-229 ◽

Cited By ~ 16

Author(s):

Sheldon Reiser ◽

Philip A. Christiansen

Keyword(s):

Amino Acids ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Neutral Amino Acids ◽

The Difference

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Laminaria japonica Extract Enhances Intestinal Barrier Function by Altering Inflammatory Response and Tight Junction-Related Protein in Lipopolysaccharide-Stimulated Caco-2 Cells

Nutrients ◽

10.3390/nu11051001 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1001 ◽

Cited By ~ 7

Author(s):

Hyo-Seon Yang ◽

Fawaz G Haj ◽

Myoungsook Lee ◽

Inhae Kang ◽

Guiguo Zhang ◽

...

Keyword(s):

Epithelial Cells ◽

Tight Junction ◽

Intestinal Epithelial Cells ◽

Physiological State ◽

Water Extract ◽

Laminaria Japonica ◽

Intestinal Barrier Function ◽

Intestinal Epithelial ◽

Water Extracts ◽

Human Intestinal Epithelial Cells

In the normal physiological state, intestinal epithelial cells act as a defensive frontline of host mucosal immunity to tolerate constant exposure to external stimuli. In this study, we investigated the potential anti-inflammatory and gut permeability protective effects of Laminaria japonica (LJ) water extract (LJE) and three types of fermented Laminaria japonica water extracts (LJE-F1, LJE-F2, and LJE-F3) in lipopolysaccharide (LPS)-stimulated Caco-2, human intestinal epithelial cells. All four extracts significantly decreased the production of nitric oxide and interleukin-6 induced by LPS stimulus. In addition, LJE and the three types of LJE-Fs also inhibited LPS-induced loss of monolayer permeability, as assessed by changes in transepithelial electrical resistance. All four LJ extracts significantly prevented the inhibition of the protein levels of occludin, whereas LJE, LJE-F1, and LJE-F3 significantly attenuated the reduction in phosphorylation of adenosine monophosphate-activated protein kinase compared with the LPS-treated group in Caco-2 cells. In conclusion, LJE and its fermented water extracts appear to have potential gut health-promoting effects by reducing inflammation and partially regulating the tight junction-related proteins in human intestinal epithelial cells. Thus, additional studies are warranted to evaluate Laminaria japonica as a therapeutic agent for inflammatory bowel diseases.

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Na+/H+ Exchanger Regulates Amino Acid-Mediated Autophagy in Intestinal Epithelial Cells

Cellular Physiology and Biochemistry ◽

10.1159/000480184 ◽

2017 ◽

Vol 42 (6) ◽

pp. 2418-2429 ◽

Cited By ~ 6

Author(s):

Huiying Shi ◽

Xinyan Zhao ◽

Zhen Ding ◽

Chaoqun Han ◽

Ye Jiang ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Epithelial Cells ◽

Intestinal Inflammation ◽

Intestinal Epithelial Cells ◽

Amino Acid Starvation ◽

Autophagic Flux ◽

Intestinal Epithelial ◽

Expression Levels ◽

Sequestosome 1

Background/Aims: Dysfunctional autophagy has been reported to be associated with aberrant intestinal metabolism. Amino acids can regulate autophagic activity in intestinal epithelial cells (IECs). Na+/H+-exchanger 3 (NHE3) has been found to participate in the absorption of amino acids in the intestine, but whether NHE3 is involved in the regulation of autophagy in IECs is unclear. Methods: In the present study, an amino acid starvation-induced autophagic model was established. Then, the effects of alanine and proline with or without the NHE inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA) were evaluated. Autophagy was examined based on the microtubule-associated light chain 3 (LC3) levels, transmission electron microscopy (TEM), tandem GFP-mCherry-LC3 construct, sequestosome-1 (SQSTM1, P62) mRNA and protein levels, and autophagy-related gene (ATG) 5, 7, and 12 expression levels. The autophagic flux was evaluated as the ratio of yellow (autophagosomes) to red (autolysosomes) LC3 puncta. Results: Following amino acid starvation, we found the LC3-II and ATG expression levels were enhanced in the IEC-18 cells. An increase in the number of autophagic vacuoles was concomitantly observed by TEM and confocal microscopy. Based on the results, supplementation with either alanine or proline depressed autophagy in the IEC-18 cells. Consistent with the elevated LC3-II levels, ATG expression increased upon NHE3 inhibition. Moreover, the mCherry-GFP-LC3 autophagic puncta representing both autophagosomes and autolysosomes per cell increased after EIPA treatment. Conclusions: These results demonstrate that NHE (most likely NHE3) may participate in the amino acid regulation of autophagy in IECs, which would aid in the design of better treatments for intestinal inflammation.

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Rational role of amino acids in intestinal epithelial cells (Review)

International Journal of Molecular Medicine ◽

10.3892/ijmm.16.2.201 ◽

2005 ◽

Author(s):

Yoshio Naomoto ◽

Tomoki Yamatsuji ◽

Kaori Shigemitsu ◽

Hidetoshi Ban ◽

Tohru Nakajo ◽

...

Keyword(s):

Amino Acids ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial

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Heat induction of heat shock protein 25 requires cellular glutamine in intestinal epithelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00225.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. C290-C299 ◽

Cited By ~ 18

Author(s):

Kittiporn Phanvijhitsiri ◽

Mark W. Musch ◽

Mark J. Ropeleski ◽

Eugene B. Chang

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Heat Shock ◽

Epithelial Cells ◽

Heat Shock Protein ◽

Cellular Response ◽

Intestinal Epithelial Cells ◽

Dependent Manner ◽

Intestinal Epithelial ◽

Heat Induction

Glutamine is considered a nonessential amino acid; however, it becomes conditionally essential during critical illness when consumption exceeds production. Glutamine may modulate the heat shock/stress response, an important adaptive cellular response for survival. Glutamine increases heat induction of heat shock protein (Hsp) 25 in both intestinal epithelial cells (IEC-18) and mesenchymal NIH/3T3 cells, an effect that is neither glucose nor serum dependent. Neither arginine, histidine, proline, leucine, asparagine, nor tyrosine acts as physiological substitutes for glutamine for heat induction of Hsp25. The lack of effect of these amino acids was not caused by deficient transport, although some amino acids, including glutamate (a major direct metabolite of glutamine), were transported poorly by IEC-18 cells. Glutamate uptake could be augmented in a concentration- and time-dependent manner by increasing either media concentration and/or duration of exposure. Under these conditions, glutamate promoted heat induction of Hsp25, albeit not as efficiently as glutamine. Further evidence for the role of glutamine conversion to glutamate was obtained with the glutaminase inhibitor 6-diazo-5-oxo-l-norleucine (DON), which inhibited the effect of glutamine on heat-induced Hsp25. DON inhibited phosphate-dependent glutaminase by 75% after 3 h, decreasing cell glutamate. Increased glutamine/glutamate conversion to glutathione was not involved, since the glutathione synthesis inhibitor, buthionine sulfoximine, did not block glutamine’s effect on heat induction of Hsp25. A large drop in ATP levels did not appear to account for the diminished Hsp25 induction during glutamine deficiency. In summary, glutamine is an important amino acid, and its requirement for heat-induced Hsp25 supports a role for glutamine supplementation to optimize cellular responses to pathophysiological stress.

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