Increased small intestinal apoptosis in coeliac disease.

Moss, Steven F.; Attia, Larry; Scholes, John V.; Walters, Julian R.F.; Holt, Peter R.

doi:10.1136/gut.39.6.811

Cited by 154 publications

(127 citation statements)

References 25 publications

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“…In certain inflammatory conditions, such as celiac disease, nematode infections, and graft-versus-host disease, the numbers of apoptotic nuclei were increased in villus epithelial cells (32)(33)(34)(35). In addition, the involvement of dysregulation of the apoptotic process in intestinal epithelial cells in inflammatory bowel diseases and colon cancer has also been suggested (36,37).…”

Section: Discussionmentioning

confidence: 96%

Intectin, a Novel Small Intestine-specific Glycosylphosphatidylinositol-anchored Protein, Accelerates Apoptosis of Intestinal Epithelial Cells

Kitazawa

Nishihara

Nambu

et al. 2004

Journal of Biological Chemistry

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Intestinal epithelial cells undergo rapid turnover and exfoliation especially at the villus tips. This process is modulated by various nutrients especially fat. Apoptosis is one of the important regulatory mechanisms of this turnover. Therefore, identification of the factors that control epithelial cell apoptosis should help us understand the mechanism of intestinal mucosal turnover. Here, we report the identification of a novel small intestine-specific member of the Ly-6 family, intectin, by signal sequence trap method. Intectin mRNA expression was exclusively identified in the intestine and localized at the villus tips of intestinal mucosa, which is known to undergo apoptosis. Intectin mRNA expression was modulated by nutrition. Intestinal epithelial cells expressing intectin were more sensitive to palmitate-induced apoptosis, compared with control intestinal epithelial cells, and such effect was accompanied by increased activity of caspase-3. Intectin expression also reduced cell-cell adhesion of intestinal epithelial cells.Intestinal epithelial cells originate from stem cells at the base of the crypt and migrate along the crypt-villus axis toward the intestinal lumen. When intestinal epithelial cells reach the luminal surface at the villus tips, they finally exfoliate into the lumen, and their cell cycle is terminated with a life span of only 3-5 days (1, 2). This constant and rapid turnover of intestinal mucosa is essential for maximal nutrient absorption, adaptation to changes in diet, and repair of mucosal injury (3).Apoptosis plays an important role in maintaining the physiological integrity of many tissues. In the intestine, apoptosis is a key regulator for the turnover of intestinal mucosa, and apoptotic intestinal epithelial cells have been detected at the villus tips of the small intestine and the colonic luminal surface (4 -6). However, the one or more underlying mechanisms of this process have not been elucidated. In this regard, it is important to identify the factors that control intestinal epithelial cell apoptosis to understand the mechanism of intestinal mucosal turnover.The present study was designed to identify a small intestinederived protein or secretory protein modulated nutritionally that is involved in the control of intestinal epithelial cell apoptosis. Using the efficient signal sequence trap (SST) 1 method (7), we identified a novel small intestine-specific GPI-anchored protein, intectin, which showed distinct localization at the villus tips of intestinal mucosa and accelerated fatty acid-induced apoptosis of intestinal epithelial cells. EXPERIMENTAL PROCEDURESCloning of Intectin cDNA-Poly(A) ϩ RNAs were extracted from the small intestinal epithelium of C57BL/6J mice under three feeding conditions; ad libitum, 24-h fasting, and 24-h fasting followed by 24-h feeding, and from the small intestinal epithelium of ad libitum-fed db/db mice. Equal amount of poly(A) ϩ RNA from each group was pooled and used as the template to synthesize complementary DNA (cDNA). To selectively clone the gen...

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Section: Discussionmentioning

confidence: 96%

Intectin, a Novel Small Intestine-specific Glycosylphosphatidylinositol-anchored Protein, Accelerates Apoptosis of Intestinal Epithelial Cells

Kitazawa

Nishihara

Nambu

et al. 2004

Journal of Biological Chemistry

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“…Finally, nickel-diaminobenzidine tetrahydrochloride was used as the chromogen for histochemical detection. 27 …”

Section: Evaluation Of Apoptosismentioning

confidence: 99%

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

et al. 1999

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Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two-thirds partial hepatectomy (PH). Because two-thirds PH is not feasible for use in humans, in the present study, we evaluated the ability of thyroid hormone (triiodothyronine [T 3 ]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T 3 initiates morphogenesis in amphibians through a process involving both cell proliferation and apoptosis, we also determined whether apoptosis might play a role in the mechanism of hepatocyte proliferation induced by T 3 . Following hepatocyte transplantation and repeated injections of T 3 , the number of transplanted hepatocytes in the liver of RSpretreated animals increased progressively to repopulate 60% to 80% of parenchymal cell mass in 60 days. We show further that T 3 treatment augments proliferation of normal hepatocytes, as evidenced by increased histone 3 mRNA and cyclin-dependent kinase 2 (cdk2) expression, and this is followed by apoptosis. These combined effects of T 3 lead to selective proliferation of transplanted hepatocytes in RS-pretreated rats, while endogenous hepatocytes, which are blocked in their proliferative capacity by RS, mainly undergo apoptosis. Thus, T 3 can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation. (HEPATOLOGY 1999;30:903-913.)A major problem in most hepatocyte transplantation studies to date has been the limited growth of transplanted cells in the recipient liver. [1][2][3][4][5] Efforts to solve this problem have generally used partial hepatectomy (PH) to remove a portion of the resident liver and thus provide a proliferative stimulus to transplanted cells. [3][4][5] Because host hepatocytes can also respond to this liver-regenerative stimulus, selective repopulation by transplanted cells does not occur under most circumstances. However, PH is not practical for routine use in human hepatocyte transplantation protocols, and thus, establishing alternative methods to stimulate hepatocyte proliferation in the context of cell transplantation is of great interest.Three experimental models of extensive liver repopulation have recently been described: the urokinase-type plasminogen activator (uPA) transgenic mouse, 6-8 the fumarylacetoacetate hydrolase (FAH) null mouse, 9,10 and the retrorsine (RS)/PH-treated rat. 11 In the uPA model, endogenous hepatocytes that have deleted the transgene, 6 or transplanted normal hepatocytes, 7,8 proliferate extensively because of continuous proteolytic destruction of resident hepatocytes expressing uPA. [6][7][8] Similarly, in FAH null mice, transplanted wild-type hepatocytes exhibit a growth advantage over enzymedeficient host cells, because the latter accumulate toxic intermedia...

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“…1 Abnormalities associated with apoptosis in the epithelium have been linked to most major GI disorders, including ischemia reperfusion injury, graft-versus-host disease, inflammatory bowel disease, necrotizing enterocolitis, celiac disease, GI infections and colorectal cancer. [2][3][4] A very intriguing feature of apoptosis in the intestine is that post-mitotic epithelial cells that migrate out of the crypts and move up the villi rapidly lose their ability to undergo apoptosis. 5 The molecular mechanism responsible for the acquisition of this highly resistant phenotype of the villus cells within a few hours of their exit from the crypts has been perplexing and has remained unidentified.…”

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confidence: 99%

Actin reorganization as the molecular basis for the regulation of apoptosis in gastrointestinal epithelial cells

et al. 2012

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The gastrointestinal (GI) epithelium is a rapidly renewing tissue in which apoptosis represents part of the overall homeostatic process. Regulation of apoptosis in the GI epithelium is complex with a precise relationship between cell position and apoptosis. Apoptosis occurs spontaneously and in response to radiation and cytotoxic drugs at the base of the crypts. By contrast, the villus epithelial cells are extremely resistant to apoptosis. The molecular mechanism underlying this loss of function of villus epithelial cells to undergo apoptosis shortly after their exit from the crypt is unknown. In this study we demonstrate for the first time, that deletion of two homologous actin-binding proteins, villin and gelsolin renders villus epithelial cells extremely sensitive to apoptosis. Ultrastructural analysis of the villin-gelsolin À/À double-knockout mice shows an abnormal accumulation of damaged mitochondria demonstrating that villin and gelsolin function on an early step in the apoptotic signaling at the level of the mitochondria. A characterization of functional and ligand-binding mutants demonstrate that regulated changes in actin dynamics determined by the actin severing activities of villin and gelsolin are required to maintain cellular homeostasis. Our study provides a molecular basis for the regulation of apoptosis in the GI epithelium and identifies cell biological mechanisms that couple changes in actin dynamics to apoptotic cell death.

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Increased small intestinal apoptosis in coeliac disease.

Cited by 154 publications

References 25 publications

Intectin, a Novel Small Intestine-specific Glycosylphosphatidylinositol-anchored Protein, Accelerates Apoptosis of Intestinal Epithelial Cells

Intectin, a Novel Small Intestine-specific Glycosylphosphatidylinositol-anchored Protein, Accelerates Apoptosis of Intestinal Epithelial Cells

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

Actin reorganization as the molecular basis for the regulation of apoptosis in gastrointestinal epithelial cells

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