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Proton Coupled Oligopeptide Transporter 1 (PepT1) Function, Regulation, and Influence on the Intestinal Homeostasis

Britta Spanier, Florian Rohm

10.1002/cphy.c170038

Source: Volume 8, Issue 2, April 2018

Published online: March 2018

Full Article on Wiley Online Library



ABSTRACT

As the organ with one of the largest surface areas facing the environment and responsible for nutrient uptake, the small intestine expresses numerous transport proteins in its brush‐border membrane for efficient absorption and supply of dietary macro‐ and micronutrients. The understanding of regulation and functional interplay of these nutrient transporters is of emerging interest in nutrition and medical physiology research in respect to development of diabetes, obesity, and inflammatory bowel disease worldwide. The peptide transporter 1 (PepT1, SLC15A1) is abundantly expressed particularly in the intestinal tract and provides highly effective transport of amino acids in the form of di‐ and tripeptides and features a substantial acceptance for structurally related compounds and drugs. These characteristics bring PepT1 into focus for nutritional and medical/pharmaceutical approaches, as it is the essential hub responsible for oral bioavailability of dietary protein/peptide supplements and peptide‐like drugs in eukaryotic organisms. Detailed analysis of molecular processes regulating PepT1 expression and function achieved in the last two decades has helped to define and use adjusting tools and to better integrate the transporter's role in cell and organ physiology. In this article, we provide an overview of the current knowledge on PepT1 function in health and disease, and on regulatory factors modulating its gene and protein expression as well as transport activity. © 2018 American Physiological Society. Compr Physiol 8:843‐869, 2018.

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Figure 1. Figure 1. Amino acid and di‐ and tripeptide transporters in the apical and basolateral membrane of mammalian enterocytes in small intestine. The brush‐border membrane contains transport proteins for acidic amino acids (EAAT3), for glycine/proline (PAT1, IMINO), for neutral amino acids (B0AT1/ACE2), for basic in exchange with neutral amino acids (b0,+AT/rBAT), and for di‐ and tripeptides (PepT1). All heterodimeric amino acid transporters only function in the presence of their heavy chain (ACE2, rBAT, or 4F2hc). Most transporters are electrogenic and couple substrate uptake with ion movement. The function of PAT1 and PepT1 is dependent on the pH gradient between gut lumen and cytoplasm, which is maintained by the sodium‐proton exchanger NHE3. The Na+ gradient on the other hand is stabilized by the Na+/K+‐ATPase. In the cytoplasm, most peptides are hydrolyzed by numerous cytosolic peptidases and the released amino acids will be exported via basolateral amino acid transporters. TAT1 exports aromatic amino acids, SNAT2 imports neutral amino acids, while LAT2/4F2hc and y + LAT1/4F2hc are responsible for exchange of neutral or basic amino acids against neutral ones. The postulated basolateral peptide transporter that allows release of small peptides and structurally related drugs into the blood stream has not been identified yet.
Figure 2. Figure 2. Tissue distribution of peptide transporters PepT1 and PepT2 in humans. The PepT1 protein is mainly expressed in the small intestine, with increasing expression from duodenum to ileum. It can also be found in low concentrations in the distal colon, in the proximal tubulus of the kidney and in bile duct, pancreas, and placenta. PepT2 is the renal isoform, predominantly expressed in the distal tubulus, but also present in brain, glia cells, lung, and mammary gland. The scheme of the human corpus is from an open source (https://pixabay.com).
Figure 3. Figure 3. Expression of PepT1 protein along the mouse small intestine and colon. Representative images of duodenum (A), jejunum (B), ileum (C), and proximal (D), middle (E), and distal (F) colon tissue. Nuclei are stained with DAPI (blue), and mouse PepT1 protein expression was detected by custom‐made anti‐mPepT1 antibody, which was used before (130). PepT1 expression increases from proximal to distal colon.
Figure 4. Figure 4. The role of PepT1 in intestinal homeostasis. The wide variety of PepT1 substrates includes exogenous oligopeptides like the C‐terminal sequence of α‐melanocyte stimulating hormone (α‐MSH) Lys‐Pro‐Val (KPV) and the dietary soy tripeptide Val‐Pro‐Tyr (VPY), as well as endogenous bacterial oligopeptides. Uptake via PepT1 of bacterial products like L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (Tri‐DAP) and muramyl dipeptide (MDP), a constituent of bacterial cell walls, is associated with the activation of mitogen‐activated protein (MAP) kinase pathway and NF‐κB, and subsequently an increase in proinflammatory cytokine expression in enterocytes. In intestinal macrophages, PepT1‐mediated uptake of bacterial products induces an increase in proinflammatory cytokine secretion that, together with the increased cytokine levels in enterocytes, may contribute to the pathogenesis or promotion of intestinal inflammation. PepT1‐mediated uptake of other bacterial peptides like N‐formyl‐Met‐Leu‐Phe (fMLF) as well as of aforementioned KPV and VPY on the other hand conveys anti‐inflammatory properties by inhibition of proinflammatory cytokine secretion due to reduced activation of NF‐κB and MAP kinase inflammatory signaling pathways. Besides these anti‐inflammatory effects associated with PepT1 transport activity, PepT1 may also directly affect bacterial‐epithelial interactions. Certain enteropathogenic bacteria attaching to enterocytes specifically via lipid rafts induce PepT1 expression in said lipid rafts. Increased intestinal PepT1 expression in turn reduces bacterial lipid raft attachment, while at the same time reducing activity of NF‐κB, MAP kinase and secretion of proinflammatory cytokines, implying an anti‐inflammatory role of PepT1 in intestinal host defense against pathogenic enterobacteria.
Figure 5. Figure 5. Functions of peptide transporter PepT1. In the last decade it became more and more obvious, that next to the transport of di‐ and tripeptides and peptidomimetic drugs, the activity pattern of PepT1 is much more complex. In distal ileum and in the colon the uptake of bacterial‐derived peptides plays a role in inflammatory processes and in the development of diseases. For stabilization of the intestinal homeostasis PepT1 is embedded in a network consisting of protein hydrolysis (peptidases), amino acid supply, mTOR signaling, protein de novo synthesis, and unfolded protein response (UPR). The analysis of its transceptor function, its regulation by micro RNAs (miRNA), and its direct protein‐protein interactions are relatively novel fields and they will improve the understanding of the peptide transporters.


Figure 1. Amino acid and di‐ and tripeptide transporters in the apical and basolateral membrane of mammalian enterocytes in small intestine. The brush‐border membrane contains transport proteins for acidic amino acids (EAAT3), for glycine/proline (PAT1, IMINO), for neutral amino acids (B0AT1/ACE2), for basic in exchange with neutral amino acids (b0,+AT/rBAT), and for di‐ and tripeptides (PepT1). All heterodimeric amino acid transporters only function in the presence of their heavy chain (ACE2, rBAT, or 4F2hc). Most transporters are electrogenic and couple substrate uptake with ion movement. The function of PAT1 and PepT1 is dependent on the pH gradient between gut lumen and cytoplasm, which is maintained by the sodium‐proton exchanger NHE3. The Na+ gradient on the other hand is stabilized by the Na+/K+‐ATPase. In the cytoplasm, most peptides are hydrolyzed by numerous cytosolic peptidases and the released amino acids will be exported via basolateral amino acid transporters. TAT1 exports aromatic amino acids, SNAT2 imports neutral amino acids, while LAT2/4F2hc and y + LAT1/4F2hc are responsible for exchange of neutral or basic amino acids against neutral ones. The postulated basolateral peptide transporter that allows release of small peptides and structurally related drugs into the blood stream has not been identified yet.


Figure 2. Tissue distribution of peptide transporters PepT1 and PepT2 in humans. The PepT1 protein is mainly expressed in the small intestine, with increasing expression from duodenum to ileum. It can also be found in low concentrations in the distal colon, in the proximal tubulus of the kidney and in bile duct, pancreas, and placenta. PepT2 is the renal isoform, predominantly expressed in the distal tubulus, but also present in brain, glia cells, lung, and mammary gland. The scheme of the human corpus is from an open source (https://pixabay.com).


Figure 3. Expression of PepT1 protein along the mouse small intestine and colon. Representative images of duodenum (A), jejunum (B), ileum (C), and proximal (D), middle (E), and distal (F) colon tissue. Nuclei are stained with DAPI (blue), and mouse PepT1 protein expression was detected by custom‐made anti‐mPepT1 antibody, which was used before (130). PepT1 expression increases from proximal to distal colon.


Figure 4. The role of PepT1 in intestinal homeostasis. The wide variety of PepT1 substrates includes exogenous oligopeptides like the C‐terminal sequence of α‐melanocyte stimulating hormone (α‐MSH) Lys‐Pro‐Val (KPV) and the dietary soy tripeptide Val‐Pro‐Tyr (VPY), as well as endogenous bacterial oligopeptides. Uptake via PepT1 of bacterial products like L‐Ala‐γ‐D‐Glu‐meso‐diaminopimelic acid (Tri‐DAP) and muramyl dipeptide (MDP), a constituent of bacterial cell walls, is associated with the activation of mitogen‐activated protein (MAP) kinase pathway and NF‐κB, and subsequently an increase in proinflammatory cytokine expression in enterocytes. In intestinal macrophages, PepT1‐mediated uptake of bacterial products induces an increase in proinflammatory cytokine secretion that, together with the increased cytokine levels in enterocytes, may contribute to the pathogenesis or promotion of intestinal inflammation. PepT1‐mediated uptake of other bacterial peptides like N‐formyl‐Met‐Leu‐Phe (fMLF) as well as of aforementioned KPV and VPY on the other hand conveys anti‐inflammatory properties by inhibition of proinflammatory cytokine secretion due to reduced activation of NF‐κB and MAP kinase inflammatory signaling pathways. Besides these anti‐inflammatory effects associated with PepT1 transport activity, PepT1 may also directly affect bacterial‐epithelial interactions. Certain enteropathogenic bacteria attaching to enterocytes specifically via lipid rafts induce PepT1 expression in said lipid rafts. Increased intestinal PepT1 expression in turn reduces bacterial lipid raft attachment, while at the same time reducing activity of NF‐κB, MAP kinase and secretion of proinflammatory cytokines, implying an anti‐inflammatory role of PepT1 in intestinal host defense against pathogenic enterobacteria.


Figure 5. Functions of peptide transporter PepT1. In the last decade it became more and more obvious, that next to the transport of di‐ and tripeptides and peptidomimetic drugs, the activity pattern of PepT1 is much more complex. In distal ileum and in the colon the uptake of bacterial‐derived peptides plays a role in inflammatory processes and in the development of diseases. For stabilization of the intestinal homeostasis PepT1 is embedded in a network consisting of protein hydrolysis (peptidases), amino acid supply, mTOR signaling, protein de novo synthesis, and unfolded protein response (UPR). The analysis of its transceptor function, its regulation by micro RNAs (miRNA), and its direct protein‐protein interactions are relatively novel fields and they will improve the understanding of the peptide transporters.
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Teaching Material

B. Spanier, F. Rohm. Proton Coupled Oligopeptide Transporter 1 (PepT1) Function, Regulation, and Influence on the Intestinal Homeostasis. Compr Physiol. 8: 2018, 843-869.

Didactic Synopsis

Major Teaching Points:

  1. Peptide transporter PepT1 is responsible for absorption of di- and tripeptides and of numerous structurally related peptidomimetic drugs into intestinal epithelia cells and regulate their bioavailability.
  2. The di- and tripeptide uptake is driven by the membrane potential in form of an inward directed proton gradient which is maintained by sodium-proton exchanger NHE3.
  3. PepT1 expression and function is controlled at the transcriptional, translational, and post-translational level.
  4. Systemic changes and compensatory processes after the loss of PepT1 are studied in various models including Caenorhabditis elegans, Mus musculus, and the human colon carcinoma cell line Caco-2.
  5. PepT1 is involved in intestinal homeostasis regarding metabolite profiles and tissue physiology, both in health and disease (inflammatory bowel disease, obesity, diabetes, and celiac disease).

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: The uptake and exchange of amino acids into gut epithelia cells and their release into the blood stream is facilitated by a set of amino acid and oligopeptide transporters. The physiological transporter functions like substrate preferences and coupling to ion gradients are described in the formal figure legend. Peptide transporter PepT1 function is strictly dependent on the pH gradient between gut lumen and cytoplasm. Most of its substrates, comprising more than 8000 di- and tripeptides, are hydrolyzed by numerous cytosolic peptidases. The released free amino acids enter cell metabolism, protein de novo synthesis or leave the cell via basolateral amino acid transporters. The transporter for the export of small peptides and structurally related drugs has not been characterized yet.

Figure 2. Teaching points: The two oligopeptide transporters PepT1 and PepT2 exhibit distinct expression patterns in humans. The PepT1 protein is mainly expressed in the small intestine, following an increasing expression gradient from proximal to distal. It can also be found in low levels in the distal colon, in the proximal tubules of the kidney and in bile duct, pancreas, and placenta. PepT2 is the renal isoform, predominantly expressed in the distal tubules of the kidney, but also present in brain, glia cells, lung, and mammary gland.

Figure 3. Teaching points: The expression of PepT1 protein along the colon in health and disease is a topic that is controversially discussed. While in some studies PepT1 protein is only present in inflamed colon tissue, a basal PepT1 expression in healthy mouse colon tissue, next to the stable expression in samples from small intestine, was shown by our group. PepT1 expression increases from proximal to distal colon.

Figure 4. Teaching points: The role of PepT1 in intestinal homeostasis. Besides dietary oligopeptides and structurally related drugs, the range of PepT1 transport substrates also contains certain bacterial products. The uptake of these oligopeptides from intestinal bacteria into intestinal epithelial cells and intestinal immune cells can cause or contribute to intestinal inflammation. There are however also other bacterial oligopeptides as well as certain dietary oligopeptides that prevent or reduce intestinal inflammation when taken up via PepT1. Besides this anti-inflammatory effects associated with its transport activity, PepT1 may also be involved in the defense against pathogenic intestinal bacteria by preventing their attachment to specific regions of the enterocyte membrane called lipid rafts.

Figure 5. Teaching points: Functions of peptide transporter PepT1. Next to its main function as transporter for di- and tripeptides, in the last years it became clear that PepT1 is a mediator between nutrient supply, protein breakdown and de novo synthesis, microbiota, and the epithelia cells. PepT1 stabilizes the intestinal homeostasis between health and disease by sensing environmental factors via its transceptor function, allows direct and indirect interaction with bacteria (e.g., by uptake of bacteria-derived peptides), and enables the treatment of selected diseases by transport of selected peptidomimetic drugs.


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Article Title: Proton Coupled Oligopeptide Transporter 1 (PepT1) Function, Regulation, and Influence on the Intestinal Homeostasis
 

How to Cite

Britta Spanier, Florian Rohm. Proton Coupled Oligopeptide Transporter 1 (PepT1) Function, Regulation, and Influence on the Intestinal Homeostasis. Compr Physiol 2018, 8: 843-869. doi: 10.1002/cphy.c170038