Regulation of intestinal mucosal growth by amino acids

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 EGF 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.

Spermidine, a sensor for antizyme 1 expression regulates intracellular polyamine homeostasis

“…We have shown that AZ1 is not only regulated at the level of frameshifting but also by amino acids involving TORC2 activity (Ray et al 2012). Amino acids like ASN and GLN repress while LYS, ARG, and VAL stimulate AZ1synthesis in EBSS (Ray et al 2012; Ray and Johnson 2013). Addition of 10 μM PUT stimulated AZ1 expression in EBSS, and both ASN and GLN decreased it.…”

Asparagine improves intestinal integrity, inhibits TLR4 and NOD signaling, and differently regulates p38 and ERK1/2 signaling in weanling piglets after LPS challenge

“…In fact, previous in vitro studies have shown that Asn protected against the induction of apoptosis in Glndeprived rat intestinal epithelial cells. 20,21 The protective effect of Asn was completely blocked by a Gln synthetase inhibitor, suggesting that the conversion of Asn to Gln is required for protection against apoptosis. 21 In addition, Asn increases ornithine decarboxylase (ODC) activity and cellular polyamine levels, and thus improves rat intestinal mucosal growth.…”

Polyamine-independent Expression of Caenorhabditis elegans Antizyme

“…This leads us to the conclusion that TOR negatively regulates antizyme levels and that TOR inhibition induces antizyme expression independent of the cellular polyamine biosynthesis. In this context, it is interesting to note that recent findings in cell culture experiments have shown the amino acids asparagine and glutamine to regulate rat antizyme1 expression by differential activation of mammalian TORC-1 and TORC-2 (53,54). Here it was shown that amino acid starvation leads to inhibition of TORC-1 signaling, whereas TORC-2 is activated.…”