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Regulation of intestinal mucosal growth by amino acids

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Abstract

Amino acids, especially glutamine (GLN) have been known for many years to stimulate the growth of small intestinal mucosa. Polyamines are also required for optimal mucosal growth, and the inhibition of ornithine decarboxylase (ODC), the first rate-limiting enzyme in polyamine synthesis, blocks growth. Certain amino acids, primarily asparagine (ASN) and GLN stimulate ODC activity in a solution of physiological salts. More importantly, their presence is also required before growth factors and hormones such as epidermal growth factor and insulin are able to increase ODC activity. ODC activity is inhibited by antizyme-1 (AZ) whose synthesis is stimulated by polyamines, thus, providing a negative feedback regulation of the enzyme. In the absence of amino acids mammalian target of rapamycin complex 1 (mTORC1) is inhibited, whereas, mTORC2 is stimulated leading to the inhibition of global protein synthesis but increasing the synthesis of AZ via a cap-independent mechanism. These data, therefore, explain why ASN or GLN is essential for the activation of ODC. Interestingly, in a number of papers, AZ has been shown to inhibit cell proliferation, stimulate apoptosis, or increase autophagy. Each of these activities results in decreased cellular growth. AZ binds to and accelerates the degradation of ODC and other proteins shown to regulate proliferation and cell death, such as Aurora-A, Cyclin D1, and Smad1. The correlation between the stimulation of ODC activity and the absence of AZ as influenced by amino acids is high. Not only do amino acids such as ASN and GLN stimulate ODC while inhibiting AZ synthesis, but also amino acids such as lysine, valine, and ornithine, which inhibit ODC activity, increase the synthesis of AZ. The question remaining to be answered is whether AZ inhibits growth directly or whether it acts by decreasing the availability of polyamines to the dividing cells. In either case, evidence strongly suggests that the regulation of AZ synthesis is the mechanism through which amino acids influence the growth of intestinal mucosa. This brief article reviews the experiments leading to the information presented above. We also present evidence from the literature that AZ acts directly to inhibit cell proliferation and increase the rate of apoptosis. Finally, we discuss future experiments that will determine the role of AZ in the regulation of intestinal mucosal growth by amino acids.

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Acknowledgments

This publication was made possible by Grants (Number DK-16505 and DK-052784) from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and by support from the Thomas A. Gerwin endowment. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Health.

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The authors declare that they have no conflict of interest.

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  1. Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN, 38163, USA

    Ramesh M. Ray & Leonard R. Johnson

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  1. Ramesh M. Ray
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  2. Leonard R. Johnson
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Correspondence to Ramesh M. Ray.

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Ray, R.M., Johnson, L.R. Regulation of intestinal mucosal growth by amino acids. Amino Acids 46, 565–573 (2014). https://doi.org/10.1007/s00726-013-1565-2

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