Glutamine is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells

Nakajo, Tohru; Yamatsuji, Tomoki; Ban, Hidetoshi; Shigemitsu, Kaori; Haisa, Minoru; Motoki, Takayuki; Noma, Kazuhiro; Nobuhisa, Tetsuji; Matsuoka, Junji; Gündüz, Mehmet; Yonezawa, Kazuyoshi; Tanaka, Noriaki; Naomoto, Yoshio

doi:10.1016/j.bbrc.2004.11.015

Cited by 79 publications

(65 citation statements)

References 31 publications

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“…Numerous other studies have confirmed the role of leucine in activating the mTOR signaling pathway in certain cells including the intestine [37][38][39]. In the presence of leucine or other recently identified amino acids such as arginine, p70 S6 kinase and eIF-4E binding protein 1 are activated by mTOR.…”

Section: Discussionmentioning

confidence: 87%

Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro

Chen¹,

Reimer²

2009

Nutrition

138

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Objective-A growing body of evidence supports an antiobesity effect of dairy products; however, the mechanisms remain unclear. The objective of this study was to explore possible intestinal mechanisms by which dairy delivers an antiobesity effect. The human intestinal cell line, NCI-H716, was used to test the hypothesis that branched-chain amino acids and dairy proteins regulate satiety hormone secretion and modulate genes involved in fatty acid and cholesterol metabolism.Methods-In dose-response (0.5%, 1.0%, 2.0%, and 3.0%) studies, the effect of leucine, isoleucine, valine, skim milk, casein, and whey on glucagon-like peptide-1 release and the expression of selected genes were tested.Results-Leucine, isoleucine, skim milk, and casein stimulated glucagon-like peptide-1 release (P < 0.05). Isoleucine and whey downregulated the expression of intestinal-type fatty acid binding protein (i-FABP), fatty acid transport protein 4 (FATP4), Niemann-Pick C-1-like-1 protein (NPC1L1), acetyl-coenzyme A carboxylase (ACC), fatty acid synthase (FAS), sterol regulatory element-binding protein-2 (SREBP-2), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR; P < 0.05). Leucine and valine downregulated the expression of NPC1L1, ACC, FAS, SREBP-2, and HMGCR (P < 0.05). Casein downregulated the expression of i-FABP, FATP4, ACC, FAS, SREBP-2, and HMGCR (P < 0.05). Skim milk downregulated the expression of ACC, FAS, and SREBP-2, but not i-FABP, FATP4, and NPC1L1.Conclusion-This work suggests that the antiobesity effect of dairy may be mediated, at least in part, by integration of events that promote glucagon-like peptide-1 secretion and inhibit expression of genes involved in intestinal fatty acid and cholesterol absorption and synthesis.

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Section: Discussionmentioning

confidence: 87%

Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro

Chen¹,

Reimer²

2009

Nutrition

138

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“…These results indicate that mTORC1 pathway activation in the Apc ⌬716 intestinal polyps is independent of Erk and AMPK signaling. Nutrients such as leucine can also activate the mTORC1 pathway (21). Starved WT mice showed reduction in the S6 phosphorylation level in the normal intestinal epithelium compared with free-feeding WT mice.…”

Section: Inhibitory Effect Of Rad001 On Polyp Formation Is Attributabmentioning

confidence: 99%

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice

Fujishita

Aoki

Lane

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

147

143

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The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status in gastrointestinal tumors has not been characterized thoroughly. We have found that the mTORC1 pathway is activated with increased expression of the mTOR protein in intestinal polyps of the Apc ⌬716 heterozygous mutant mouse, a model for human familial adenomatous polyposis. An 8-week treatment with RAD001 (everolimus) suppressed the mTORC1 activity in these polyps and inhibited proliferation of the adenoma cells as well as tumor angiogenesis, which significantly reduced not only the number of polyps but also their size. ␤-Catenin knockdown in the colon cancer cell lines reduced the mTOR level and thereby inhibited the mTORC1 signaling. These results suggest that the Wnt signaling contributes to mTORC1 activation through the increased level of mTOR and that the activation plays important roles in the intestinal polyp formation and growth. Indeed, longterm RAD001 treatment significantly reduced mortality of the Apc ⌬716 mice. Thus, we propose that the mTOR inhibitors may be efficacious for therapy and prevention of colonic adenomas and cancers with Wnt signaling activation.adenoma ͉ colon cancer ͉ mammalian target of rapamycin ͉ RAD001 ͉ rapamycin

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“…Previous studies have reported that glutamine can inhibit mTORC1 activity in vitro using cultured cells deprived of serum and amino acids, a nonphysiological condition (Nakajo et al 2005;Deldicque et al 2008). We questioned if glutamine infused into the rat hippocampus can have similar effect in vivo, as assessed by phosphorylation of the known downstream targets ribosomal S6 kinase (S6K) and ribosomal protein S6 (S6).…”

Section: Glutamine Inhibits Mtorc1 Activity In Vivomentioning

confidence: 98%

“…However, other studies have demonstrated that glutamine can either inhibit (Nakajo et al 2005;Deldicque et al 2008) or stimulate (Nicklin et al 2009;Chiu et al 2012;Willems et al 2013) mTORC1 activity, although the mechanism(s) through which this is accomplished are not yet clear. Although these and other studies that have examined the influence of glutamine on mTORC1 activity using cells cultured in vitro, they were typically carried out using serum-and/or amino acid-free conditions to induce a state of starvation.…”

mentioning

confidence: 99%

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

et al. 2015

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The mechanistic Target of Rapamycin Complex 1 (mTORC1), a key regulator of protein synthesis and cellular growth, is also required for long-term memory formation. Stimulation of mTORC1 signaling is known to be dependent on the availability of energy and growth factors, as well as the presence of amino acids. In vitro studies using serum-and amino acidstarved cells have reported that glutamine addition can either stimulate or repress mTORC1 activity, depending on the particular experimental system that was used. However, these experiments do not directly address the effect of glutamine on mTORC1 activity under physiological conditions in nondeprived cells in vivo. We present experimental results indicating that intrahippocampal administration of glutamine to rats reduces mTORC1 activity. Moreover, post-training administration of glutamine impairs long-term spatial memory formation, while coadministration of glutamine with leucine had no influence on memory. Intracellular recordings in hippocampal slices showed that glutamine did not alter either excitatory or inhibitory synaptic activity, suggesting that the observed memory impairments may not result from conversion of glutamine to either glutamate or GABA. Taken together, these findings indicate that glutamine can decrease mTORC1 activity in the brain and may have implications for treatments of neurological diseases associated with high mTORC1 signaling.

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Glutamine is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells

Cited by 79 publications

References 31 publications

Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro

Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

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Glutamine is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells

Cited by 79 publications

References 31 publications

Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro

Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc Δ716 mice

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

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Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice