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Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel Diseases

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Abstract

Intestinal absorption of dietary amino acids/peptides is essential for protein homeostasis, which in turn is crucial for maintaining health as well as restoration of health from significant diseases. Dietary amino acids/peptides are absorbed by unique transporter processes present in the brush border membrane of absorptive villus cells, which line the entire length of the intestine. To date, the only nutrient absorptive system described in the secretory crypt cells in the mammalian intestine is the one that absorbs the amino acid glutamine. Majority of the amino acid transporters are sodium dependent and therefore require basolateral membrane Na‐K‐ATPase to maintain an efficient transcellular Na gradient for their activity. These transport processes are tightly regulated by various cellular and molecular mechanisms that facilitate their optimal activity during normal physiological processes. Malabsorption of amino acids, recently described in pathophysiological states such as in inflammatory bowel disease (IBD), is undoubtedly responsible for the debilitating symptoms of IBD such as malnutrition, weight loss and ultimately a failure to thrive. Also recently, in vivo models of IBD and in vitro studies have demonstrated that specific immune‐inflammatory mediators/pathways regulate specific amino acid transporters. This provides possibilities to derive novel nutrition and immune‐based treatment options for conditions such as IBD. © 2020 American Physiological Society. Compr Physiol 10:673‐686, 2020.

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Figure 1. Figure 1. Intestinal epithelium is lined by columnar epithelial cells that originate from the intestinal stem cells located in the crypt. These mature and differentiate into absorptive villus cells that express many amino acid transporters in their brush border membrane (BBM). The lone amino acid transporter expressed in the crypt BBM is SN2 which is a Na‐glutamine cotransporter. Intraepithelial lymphocytes are represented by cells shaded green.
Figure 2. Figure 2. Proposed models for leptin‐mediated hormonal regulation of amino acid transporter activity in the mammalian intestine. (A) Leptin hormone activates PI3K‐mTOR1, which in turn activates SK6 leading to the increase in transcription of AAT. (B) Alternate pathway of leptin mediated AAT activation is through phosphorylation of STAT3, which increases the transcription of AAT. AAT, amino acid transporters; PI3K, phosphoinositide 3‐kinase; mTORC1, mechanistic target of rapamycin complex1; S6K1, ribosomal protein S6 kinase beta‐1; ERK, extracellular‐signal‐regulated kinase; AP1, activator protein 1; TYR, tyrosine; P, phosphorylated protein; JAK, Janus kinase (JAK); STAT3, signal transducer and activator of transcription.
Figure 3. Figure 3. Regulation of glutamine absorption in small intestinal villus and crypt cells during chronic intestinal inflammation. Na‐glutamine cotransporter B0AT1 in villus cells was inhibited secondary to reduced cotransporter numbers and reduced Na‐K‐ATPase activity, while SNAT5/SN2 was stimulated secondary to increased transporter affinity and increased Na‐K‐ATPase activity.
Figure 4. Figure 4. In a rabbit model of chronic intestinal inflammation, B0AT1‐mediated glutamine malabsorption was ameliorated by treatment by a broad spectrum immune modulator, methylprednisolone (MP), inhibition of inducible nitric oxide (iNO) production with LNIL, a specific inhibitor of iNO synthase; inhibition of activated mast cells with ketotifen, a mast cell membrane stabilizer; inhibition of prostaglandin production with Piroxicam (PRX) a cyclooxygenase (COX) pathway inhibitor. Treatment with each of these pharmaceutical agents restored the activity of the Na‐glutamine cotransporter B0AT1 and Na‐K‐ATPase, thereby reversing the malabsorption of glutamine during chronic enteritis. These observations indicate that reduction of production or release of immune‐inflammatory mediators by immunocytes such as mast cells and/or epithelial cells (e.g., prostaglandins) by specific agents reverses the inhibition of B0AT1 during chronic enteritis.
Figure 5. Figure 5. Model of immune regulation of B0AT1 in villus and SN2 in crypt cells in the intestine. The two‐primary sodium‐glutamine cotransporters are not only unique to villus (B0AT1) and crypt (SN2) cells, but the mechanism of their alteration during chronic enteritis is also quite novel. During chronic intestinal inflammation, upstream, both B0AT1 and SN2 are regulated by common inflammatory pathways, namely, mast cells, nitric oxide (NO) and arachidonic acid from the plasma membrane released by phospholipase A2 (PLAP2). But downstream, the immune regulation of these two transporters is quite unique: SN2 in crypt cells is regulated by the lipoxygenase (LOX) pathway, most likely by leukotrieneD4 (LTD4), whereas, B0AT1 in villus cells is regulated by the cyclooxygenase (COX) pathway, most likely by prostaglandin E2 (PGE2).
Figure 6. Figure 6. In intestinal epithelial cells (IEC‐18 cells), the mechanism of LTD4 mediated inhibition of Na‐alanine cotransporter, ASCT1, is via the activation of PKC and PKA pathways through the phosphorylation of an intermediate protein RKIP. LTD4, leukotriene D4; PKC, protein kinase C; RKIP, Raf kinase inhibitory protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.


Figure 1. Intestinal epithelium is lined by columnar epithelial cells that originate from the intestinal stem cells located in the crypt. These mature and differentiate into absorptive villus cells that express many amino acid transporters in their brush border membrane (BBM). The lone amino acid transporter expressed in the crypt BBM is SN2 which is a Na‐glutamine cotransporter. Intraepithelial lymphocytes are represented by cells shaded green.


Figure 2. Proposed models for leptin‐mediated hormonal regulation of amino acid transporter activity in the mammalian intestine. (A) Leptin hormone activates PI3K‐mTOR1, which in turn activates SK6 leading to the increase in transcription of AAT. (B) Alternate pathway of leptin mediated AAT activation is through phosphorylation of STAT3, which increases the transcription of AAT. AAT, amino acid transporters; PI3K, phosphoinositide 3‐kinase; mTORC1, mechanistic target of rapamycin complex1; S6K1, ribosomal protein S6 kinase beta‐1; ERK, extracellular‐signal‐regulated kinase; AP1, activator protein 1; TYR, tyrosine; P, phosphorylated protein; JAK, Janus kinase (JAK); STAT3, signal transducer and activator of transcription.


Figure 3. Regulation of glutamine absorption in small intestinal villus and crypt cells during chronic intestinal inflammation. Na‐glutamine cotransporter B0AT1 in villus cells was inhibited secondary to reduced cotransporter numbers and reduced Na‐K‐ATPase activity, while SNAT5/SN2 was stimulated secondary to increased transporter affinity and increased Na‐K‐ATPase activity.


Figure 4. In a rabbit model of chronic intestinal inflammation, B0AT1‐mediated glutamine malabsorption was ameliorated by treatment by a broad spectrum immune modulator, methylprednisolone (MP), inhibition of inducible nitric oxide (iNO) production with LNIL, a specific inhibitor of iNO synthase; inhibition of activated mast cells with ketotifen, a mast cell membrane stabilizer; inhibition of prostaglandin production with Piroxicam (PRX) a cyclooxygenase (COX) pathway inhibitor. Treatment with each of these pharmaceutical agents restored the activity of the Na‐glutamine cotransporter B0AT1 and Na‐K‐ATPase, thereby reversing the malabsorption of glutamine during chronic enteritis. These observations indicate that reduction of production or release of immune‐inflammatory mediators by immunocytes such as mast cells and/or epithelial cells (e.g., prostaglandins) by specific agents reverses the inhibition of B0AT1 during chronic enteritis.


Figure 5. Model of immune regulation of B0AT1 in villus and SN2 in crypt cells in the intestine. The two‐primary sodium‐glutamine cotransporters are not only unique to villus (B0AT1) and crypt (SN2) cells, but the mechanism of their alteration during chronic enteritis is also quite novel. During chronic intestinal inflammation, upstream, both B0AT1 and SN2 are regulated by common inflammatory pathways, namely, mast cells, nitric oxide (NO) and arachidonic acid from the plasma membrane released by phospholipase A2 (PLAP2). But downstream, the immune regulation of these two transporters is quite unique: SN2 in crypt cells is regulated by the lipoxygenase (LOX) pathway, most likely by leukotrieneD4 (LTD4), whereas, B0AT1 in villus cells is regulated by the cyclooxygenase (COX) pathway, most likely by prostaglandin E2 (PGE2).


Figure 6. In intestinal epithelial cells (IEC‐18 cells), the mechanism of LTD4 mediated inhibition of Na‐alanine cotransporter, ASCT1, is via the activation of PKC and PKA pathways through the phosphorylation of an intermediate protein RKIP. LTD4, leukotriene D4; PKC, protein kinase C; RKIP, Raf kinase inhibitory protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.
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Teaching Material

Soudamani Singh, Subha Arthur, and Uma Sundaram. Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel. Compr Physiol 10 : 2020, 673-686.

Didactic Synopsis

 

Mammalian intestine is the principal site of protein digestion and absorption processes. The intestinal epithelial cells, mainly villus cells, are equipped with a range of transporter proteins, which efficiently adsorb the digested dietary proteins in the form of amino acids and peptides. Specific amino acid transporter proteins appear to be targets for regulation by inflammatory mediators in conditions such as IBD that affect their absorption. Malabsorption of these important amino acids in conditions such as IBD severely compromise the restoration of overall health despite the existence of treatment options for these conditions. Thus, it is important to understand the regulation of intestinal amino acid absorption in the context of intestinal inflammation as it provides the necessary knowledge to formulate novel efficacious treatment modalities for this incurable lifelong condition.


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Soudamani Singh, Subha Arthur, Uma Sundaram. Mechanisms of Regulation of Transporters of Amino Acid Absorption in Inflammatory Bowel Diseases. Compr Physiol 2020, 10: 673-686. doi: 10.1002/cphy.c190016