Protein starvation and the small intestine

Hill, Rolla B.; Prosper, Jacques; Hirschfield, Jan S.; Kern, Fred

doi:10.1016/0014-4800(68)90006-3

Cited by 39 publications

(5 citation statements)

References 7 publications

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“…The small intestinal mucosa resists atrophy during protein deprivation for a longer time than most other tissues [24]. Major structural features of the intestinal mucosa, including villous height, crypt depth, epithelia cell number, and allocation of various cell lineages, are minimally, if at all altered (at least initially) by protein deficiency or starvation in experimental murine models [25], [26], [27], [28]. Mechanisms that may account for the preservation of intestinal architecture are not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Cell Kinase Is a Novel Participant in Intestinal Cell Signaling Responses to Protein Malnutrition

et al. 2014

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Nutritional deficiency and stress can severely impair intestinal architecture, integrity and host immune defense, leading to increased susceptibility to infection and cancer. Although the intestine has an inherent capability to adapt to environmental stress, the molecular mechanisms by which the intestine senses and responds to malnutrition are not completely understood. We hereby report that intestinal cell kinase (ICK), a highly conserved serine/threonine protein kinase, is a novel component of the adaptive cell signaling responses to protein malnutrition in murine small intestine. Using an experimental mouse model, we demonstrated that intestinal ICK protein level was markedly and transiently elevated upon protein deprivation, concomitant with activation of prominent pro-proliferation and pro-survival pathways of Wnt/β-catenin, mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and protein kinase B (PKB/Akt) as well as increased expression of intestinal stem cell markers. Using the human ileocecal epithelial cell line HCT-8 as an in vitro model, we further demonstrated that serum starvation was able to induce up-regulation of ICK protein in intestinal epithelial cells in a reversible manner, and that serum albumin partially contributed to this effect. Knockdown of ICK expression in HCT-8 cells significantly impaired cell proliferation and down-regulated active β-catenin signal. Furthermore, reduced ICK expression in HCT-8 cells induced apoptosis through a caspase-dependent mechanism. Taken together, our findings suggest that increased ICK expression/activity in response to protein deprivation likely provides a novel protective mechanism to limit apoptosis and support compensatory mucosal growth under nutritional stress.

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Section: Discussionmentioning

confidence: 99%

Intestinal Cell Kinase Is a Novel Participant in Intestinal Cell Signaling Responses to Protein Malnutrition

et al. 2014

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“…Impairment of the intraluminal mucin layer due to malnutrition was first experimentally described in the 1960s with the demonstration of a variable decrease in goblet cell number in both malnourished rats (17,20) and pigs (21), although these changes were not well characterized. Mucous globules have been found to be smaller (17) with a reduction in mucin proteins in the proximal and mid-intestinal segments demonstrated in calorie-restricted rats fed 50% of the diet consumed by age-matched controls (16). Several additional experimental models have demonstrated loss of goblet cells throughout the small intestine and colon.…”

Section: The Role Of the Supraepithelial Mucous Layer And Goblet Cell...mentioning

confidence: 99%

Starved Guts

Attia¹,

Feenstra

Swain

et al. 2017

J. pediatr. gastroenterol. nutr.

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Malnutrition contributes significantly to death and illness worldwide and especially to the deaths of children younger than 5 years. The relation between intestinal changes in malnutrition and morbidity and mortality has not been well characterized; however, recent research indicates that the functional and morphologic changes of the intestine secondary to malnutrition itself contribute significantly to these negative clinical outcomes and may be potent targets of intervention. The aim of this review was to summarize current knowledge of experimental and clinically observed changes in the intestine from malnutrition preclinical models and human studies. Limited clinical studies have shown villous blunting, intestinal inflammation, and changes in the intestinal microbiome of malnourished children. In addition to these findings, experimental data using various animal models of malnutrition have found evidence of increased intestinal permeability, upregulated intestinal inflammation, and loss of goblet cells. More mechanistic studies are urgently needed to improve our understanding of malnutrition-related intestinal dysfunction and to identify potential novel targets for intervention.

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“…It was demonstrated that the enzymatic activity and mRNA of Phgdh increased quickly in rats fed a protein-free diet [ 45 , 46 ], although the functional significance of Phgdh induction by a protein-free diet has remained unclear for a long time. The intake of a protein-free diet was shown to impair the morphological architecture and function of the intestine [ 47 ], while a recent study observed that oral supplementation of Ser maintained morphological and functional integrity of the intestine and prevented diarrhea incidence in piglets [ 42 ]. Given these previous observations, together with the present findings, the intake of a protein-free diet appears to be rapidly sensed by hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation

et al. 2021

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L-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (Phgdh). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific Phgdh KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that Phgdh-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation.

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Protein starvation and the small intestine

Cited by 39 publications

References 7 publications

Intestinal Cell Kinase Is a Novel Participant in Intestinal Cell Signaling Responses to Protein Malnutrition

Intestinal Cell Kinase Is a Novel Participant in Intestinal Cell Signaling Responses to Protein Malnutrition

Starved Guts

Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation

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