Glucagon‐like Peptide‐2 and the Regulation of Intestinal Growth and Function

Brubaker, Patricia L.

doi:10.1002/cphy.c170055

Cited by 87 publications

(76 citation statements)

References 381 publications

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“…The role of the IGF‐1R in CD36 expression was also confirmed in the human intestinal epithelial Caco‐2BBE cells in vitro. These findings are consistent with the known requirement for both IGF‐1 and the IE‐IGF‐1R in the intestinotrophic functions of GLP‐2 19 . The involvement of the IE‐IGF‐1R in the enterocyte lipid signaling pathway is also not surprising, as insulin stimulates the translocation of CD36 from endosomes to the plasma membrane in cardiomyocytes 45 .…”

Section: Discussionsupporting

confidence: 84%

“…In addition to diet, other modulators of the intestinal lipid processing pathway are known. For example, glucagon‐like peptide‐2 (GLP‐2) is an intestinotrophic hormone that is endogenously secreted by the intestinal enteroendocrine L cell in response to fat ingestion and which, following exogenous administration, increases postprandial lipid absorption through enhanced CD36 glycosylation, leading to increased CM assembly and secretion 19,20 . However, the precise mechanism underlying this effect is still unclear, as the GLP‐2 receptor is not located on the enterocytes,21‐23 thus necessitating the actions of downstream mediators.…”

Section: Introductionmentioning

confidence: 99%

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Requirement for the intestinal epithelial insulin‐like growth factor‐1 receptor in the intestinal responses to glucagon‐like peptide‐2 and dietary fat

et al. 2020

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Abbreviations: APO, apolipoprotein; CD36, cluster-of-differentiation 36; DFTT, duodenal fat tolerance test; FATP-4, fatty acid transfer protein-4; h(GLY 2 ) GLP-2, human glycine 2 -glucagon-like peptide-2; IE-IGF-1R, intestinal epithelial-insulin-like growth factor-1 receptor; KO, knockout; MTP, microsomal triglyceride transfer protein; OFTT, oral fat tolerance test; WD, Western diet. AbstractThe intestinal hormone, glucagon-like peptide-2 (GLP-2), enhances the enterocyte chylomicron production. However, GLP-2 is known to require the intestinal-epithelial insulin-like growth factor-1 receptor (IE-IGF-1R) for its other actions to increase intestinal growth and barrier function. The role of the IE-IGF-1R in enterocyte lipid handling was thus tested in the GLP-2 signaling pathway, as well as in response to a Western diet (WD). IE-IGF-1R knockout (KO) and control mice were treated for 11 days with h(GLY 2 )GLP-2 or fed a WD for 18 weeks followed by a duodenal fat tolerance test with C 14 -labeled triolein. Human Caco-2BBE cells were treated with an IGF-1R antagonist or signaling inhibitors to determine triglyceride-associated protein expression. The IE-IGF-1R was required for GLP-2-induced increases in CD36 and FATP-4 in chow-fed mice, and for expression in vitro; FATP-4 also required PI3K/Akt. Although WD-fed IE-IGF-1R KO mice demonstrated normal CD36 expression, the protein was incorrectly localized 2h post-duodenal fat administration.IE-IGF-1R KO also prevented the WD-induced increase in MTP and decrease in APOC3, increased jejunal mucosal C 14 -fat accumulation, and elevated plasma triglyceride and C 14 -fat levels. Collectively, these studies elucidate new roles for the IE-IGF-1R in enterocyte lipid handling, under basal conditions and in response to GLP-2 and WD-feeding.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Requirement for the intestinal epithelial insulin‐like growth factor‐1 receptor in the intestinal responses to glucagon‐like peptide‐2 and dietary fat

et al. 2020

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“…GLP-1 and GLP-2 are secreted in response to ingested nutrients, including glucose and fat, and their main biological actions are to enhance insulin secretion and intestinal epithelial growth, respectively 19 . The growth-stimulating effects of GLP-2 accompany nutrient ingestion and result from both increased epithelial proliferation and decreased apoptosis 20 . GLP-2 also enhances nutrient digestion and absorption, increases intestinal transit time, increases intestinal blood flow, improves epithelial barrier function, and enhances immune protection by increasing Paneth cell function.…”

Section: Paracrine Actions Of Eecsmentioning

confidence: 99%

“…Despite the prominent effects of GLP-2 on the intestinal epithelium, these actions appear to be indirect because GLP-2 receptors are not expressed on intestinal stem cells (either Lgr5+ crypt base or in Bmi1+ cells that comprise the proliferative reserve stem cell population) 20 . Although GLP-2 receptors are expressed almost exclusively in the gastrointestinal tract, they are found on 3 distinct cell types, but not intestinal epithelial cells.…”

Section: Paracrine Actions Of Eecsmentioning

confidence: 99%

Neuropods

Liddle

2019

Cellular and Molecular Gastroenterology and Hepatology

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Enteroendocrine cells (EECs) are sensory cells of the gut that communicate by releasing hormones locally through paracrine action or into the blood stream. Recently it has been discovered that EECs possess cytoplasmic processes known as neuropods that extend to distant cells including nerves. Thus, EECs regulate ingestive behavior through local, hormonal and neural signaling. Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Most EECs reside in the mucosal lining of the stomach or intestine and sense food in the gut lumen. Food signals stimulate the release of hormones into the paracellular space where they either act locally or are taken up into the blood and circulate to distant organs. It recently was recognized that many EECs possess basal processes known as neuropods that not only contain hormones but also connect to nerves. This review describes how neuropods contribute to EEC function beyond typical hormonal actions. For example, gastrointestinal hormones not only act on distant organs, but, through neuropods, some act locally to stimulate other mucosal cells such as intestinal stem cells, enterocytes, or other EECs. With the recent discovery that EECs communicate directly with enteric nerves, EECs not only have the ability to sense food and bacteria in the gastrointestinal tract, but can communicate these signals directly to the nervous system.

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“…GLP-2 exerts its functions through the 7-transmembrane G protein coupled GLP-2 receptor (GLP-2R) and the expression of GLP-2R is largely confined to gastrointestinal tract, with the highest level in the jejunum (i.e. jejunum > duodenum/ileum > colon > stomach) 7 . Studies have shown that intestinal crypt epithelial cell and intestinal villus epithelial cells do not express the GLP-2R, while intestinal stromal cell (such as intestinal subepithelial myofibroblasts, ISEMFs) do express GLP-2R.…”

Section: Introductionmentioning

confidence: 99%

Exosomes-mediated Transfer of miR-125a/b in Cell-to-cell Communication: A Novel Mechanism of Genetic Exchange in the Intestinal Microenvironment

Cheng¹,

Wang²,

Zhao³

et al. 2020

Theranostics

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Glucagon-like peptide-2 (GLP-2), a key factor in intestinal rehabilitation therapy of short bowel syndrome (SBS), may require cell-to-cell communication to exert its biological functions. However, understanding of the mechanism remains elusive. Here, we report participation of exosomal miR-125a/b in GLP-2 mediated intestinal epithelial cells-myofibroblasts cross-talk in intestinal microenvironment. Methods: The effects of GLP-2 on the proliferation and apoptosis of intestinal epithelial cells in SBS rat models were evaluated. Exosomes were extracted from residual jejunum tissue of GLP-2 or vehicle treated SBS rats using ultracentrifugation method, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting. miRNA sequencing combined with qRT-PCR validation were used to identify differentially expressed miRNAs. miRNAs, which might be involved in proliferation and apoptosis of intestinal epithelial cells, were screened and further verified by miRNA functional experiments. Moreover, the proliferation-promoting and anti-apoptosis effects of GLP-2 on intestinal myofibroblasts, which expressing GLP-2 receptor, and whether GLP-2 could influence the content of miRNAs in the derived exosomes were studied. The downstream pathways were explored by miRNA function recovery experiment, luciferase reporter assay, pull down experiment, knockdown and overexpression of target gene and other experiments based on the bioinformatics prediction of miRNA target gene. Results: GLP-2 significantly promoted intestinal growth, facilitated the proliferation of intestinal crypt epithelial cells and inhibited the apoptosis of intestinal villi epithelial cells in type II SBS rats. GLP-2 significantly down-regulated exosomal miR-125a/b both in residual jejunums derived exosomes and in exosomes secreted by GLP-2R positive cells. Exosomal miR-125a/b was responsible for GLP-2 mediated intestinal epithelial cells proliferation promotion and apoptosis attenuation. miR-125a/b inhibited the proliferation and promotes apoptosis of intestinal epithelial cells by suppressing the myeloid cell leukemia-1 (MCL1). Conclusions: miR-125a/b shuttled by intestinal myofibroblasts derived exosomes regulate the proliferation and apoptosis of intestinal epithelial cells. GLP-2 treatment significantly decreases the level of miR-125a/b in the exosomes of intestinal myofibroblasts. miR-125a/b modulates the proliferation and apoptosis of intestinal epithelial cells by targeting the 3'UTR region of MCL1. Hence, this study indicates a novel mechanism of genetic exchange between cells in intestinal microenvironment.

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Glucagon‐like Peptide‐2 and the Regulation of Intestinal Growth and Function

Cited by 87 publications

References 381 publications

Requirement for the intestinal epithelial insulin‐like growth factor‐1 receptor in the intestinal responses to glucagon‐like peptide‐2 and dietary fat

Requirement for the intestinal epithelial insulin‐like growth factor‐1 receptor in the intestinal responses to glucagon‐like peptide‐2 and dietary fat

Neuropods

Exosomes-mediated Transfer of miR-125a/b in Cell-to-cell Communication: A Novel Mechanism of Genetic Exchange in the Intestinal Microenvironment

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