Growth factor regulation of PC4/TIS7, an immediate early gene expressed during gut adaptation after resection

Swietlicki, Elzbieta A.; Iordanov, Hristo; Fritsch, Christine; Lu, Yi; Levin, Levin; Rubin, Deborah C.

doi:10.1177/0148607103027002123

Cited by 20 publications

(22 citation statements)

References 47 publications

(61 reference statements)

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“…These findings are suggestive of a novel pathway of hormonal-neural signaling in which the administration of GLP-2 activates enteric neuronal activity, stimulating the release of as yet undefined mediators that induce crypt cell proliferation. An additional possibility is that GLP-2 actions are mediated through an uncharacterized GLP-2-sensitive receptor, because additions of the ligand have been shown to prolong the survival of cultured IEC-18 cells despite the fact that these cells do not express the characterized GLP-2 receptor and have no neuronal input (46).…”

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Martin¹,

Wallace²,

Sigalet³

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

135

121

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Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 μg·kg−1·h−1 GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals ( P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression ( P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.

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Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Martin¹,

Wallace²,

Sigalet³

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

135

121

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“…These findings imply an indirect model for GLP-2 action whereby GLP-2R activation liberates downstream mediators which act on as yet unidentified pathways to promote crypt cell proliferation and inhibition of apoptosis (86). A number of GLP-2-regulated genes have been identified (87,88); however, the principal downstream targets for GLP-2 action in the gut remain unknown. Although GLP-2 activates immediate early gene expression and reduces apoptosis in heterologous cells expressing a transfected GLP-2 receptor (89 -91), whether the endogenous intestinal GLP-2R is coupled to identical signal transduction pathways remains to be determined.…”

Section: Glp-2mentioning

confidence: 99%

Minireview: Glucagon-Like Peptides Regulate Cell Proliferation and Apoptosis in the Pancreas, Gut, and Central Nervous System

2004

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Gut peptides exert diverse effects regulating satiety, gastrointestinal motility and acid secretion, epithelial integrity, and both nutrient absorption and disposal. These actions are initiated by activation of specific G protein-coupled receptors and may be mediated by direct or indirect effects on target cells. More recent evidence demonstrates that gut peptides, exemplified by glucagon-like peptides-1 and 2 (GLP-1 and GLP-2), directly regulate signaling pathways coupled to cell proliferation and apoptosis. GLP-1 receptor activation enhances beta-cell proliferation and promotes islet neogenesis via activation of pdx-1 expression. The proliferative effects of GLP-1 appear to involve multiple intracellular pathways, including stimulation of Akt, activation of protein kinase Czeta, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in beta-cells and neurons via increased levels of cAMP leading to cAMP response element binding protein activation, enhanced insulin receptor substrate-2 activity and, ultimately, activation of Akt. These actions of GLP-1 are reflected by expansion of beta-cell mass and enhanced resistance to beta-cell injury in experimental models of diabetes in vivo. GLP-2 also promotes intestinal cell proliferation and confers resistance to cellular injury in a variety of cell types. Administration of GLP-2 to animals with experimental intestinal injury promotes regeneration of the gastrointestinal epithelial mucosa and confers resistance to apoptosis in an indirect manner via yet-to-be identified GLP-2 receptor-dependent regulators of mucosal growth and cell survival. These proliferative and antiapoptotic actions of GLP-1 and GLP-2 may contribute to protective and regenerative actions of these peptides in human subjects with diabetes and intestinal disorders, respectively.

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“…The effects of GLP-2 appear to be transduced by a specific G protein-coupled receptor (30,32) localized to the enteric nervous system and select brain regions, including the hippocampus, the dorsal medial hypothalamus, and areas of the brainstem (6,27,43). Actions of GLP-2 in the gastrointestinal tract appear to be mediated primarily through enteric neuronal signaling, although this remains controversial (6,40,44).…”

mentioning

confidence: 99%

Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome

Martin¹,

Wallace²,

Hartmann³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

123

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Glucagon-like peptide-2 (GLP-2) is an enteroendocrine peptide that is released in response to luminal nutrients and has unique trophic actions in the gastrointestinal tract. These features suggest GLP-2 may be important in controlling intestinal adaptation. We examined the relationship over time of GLP-2 production and adaptation to intestinal resection, the effects of resection-induced malabsorption on GLP-2 production, and the correlation of endogenous serum GLP-2 levels with adaptation as measured by crypt-cell proliferation (CCP). We initially examined the effect of nutrient malabsorption, induced by a 90% resection of the proximal intestine studied on day 4, on the time course and levels of GLP-2 release. Secondly, the degree of malabsorption was varied by performing intestinal transection or 50, 75, or 90% resection of proximal small intestine. Finally, the relationship of GLP-2 levels over time with adaptation to a 90% resection was examined by determining GLP-2 levels on days 7, 14, and 28, and correlating this with intestinal adaptation, as assessed by morphology and CCP rate. A 90% resection significantly increased basal and postprandial GLP-2 levels, with a net increase in nutrient-stimulated exposure over 90 min; GLP-2 exposure (integrated levels vs. time) increased 12.7-fold in resected animals (P< 0.001). Basal and postprandial GLP-2 levels significantly correlated with the magnitude of intestinal resection (r(2) = 0.71; P < 0.001), CCP (r(2) = 0.48; P < 0.005), and nutrient malabsorption (protein, P < 0.001; fat, P < 0.005). The increase in CCP was maintained to 28 days after small bowel resection and was associated with an ongoing elevation in GLP-2 release. These findings suggest that GLP-2 is important in initiating and maintaining the small intestinal adaptive response to resection.

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Growth factor regulation of PC4/TIS7, an immediate early gene expressed during gut adaptation after resection

Abstract: These results suggest that PC4/TIS7 plays a role in intracellular signaling in the intestinal epithelium during the adaptive response, possibly as a common downstream effector for several intestinotrophic growth factors.

Cited by 20 publications

References 47 publications

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome

Minireview: Glucagon-Like Peptides Regulate Cell Proliferation and Apoptosis in the Pancreas, Gut, and Central Nervous System

Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome

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