Medical Physiology, 3rd Edition

Protein, Peptide, and Amino-Acid Absorption

Absorption of whole protein by apical endocytosis occurs primarily during the neonatal period

During the postnatal period, intestinal epithelial cells absorb protein by endocytosis, a process that provides a mechanism for transfer of passive immunity from mother to child. The uptake of intact protein by the epithelial cell ceases by the sixth month; the cessation of this protein uptake, called closure, is hormonally mediated. For example, administration of corticosteroids during the postnatal period induces closure and reduces the time that the intestine can absorb significant amounts of whole protein.

The adult intestine can absorb finite amounts of intact protein and polypeptides. Uncertainty exists regarding the cellular route of absorption, as well as the relationship of the mechanism of protein uptake in adults to that in neonates. Enterocytes can take up by endocytosis a small amount of intact protein, most of which is degraded in lysosomes (see Fig. 45-7). A small amount of intact protein appears in the interstitial space. The uptake of intact protein also occurs through a second, more specialized route. In the small intestine, immediately overlying Peyer's patches (follicles of lymphoid tissue in the lamina propria), M cells replace the usual enterocytes on the surface of the gut. M cells have few microvilli and are specialized for protein uptake. They have limited ability for lysosomal protein degradation; rather, they package ingested proteins (i.e., antigens) in clathrin-coated vesicles, which they secrete at their basolateral membranes into the lamina propria. There, immunocompetent cells process the target antigens and transfer them to lymphocytes to initiate an immune response. Although protein uptake in adults may not have nutritional value, such uptake is clearly important in mucosal immunity and probably is involved in one or more disease processes.

The apical absorption of dipeptides, tripeptides, and tetrapeptides occurs via an H+-driven cotransporter

Virtually all absorbed protein products exit the villous epithelial cell and enter the blood as individual amino acids. Substantial portions of these amino acids are released in the lumen of the small intestine by luminal proteases and brush-border peptidases and, as we discuss below, move across the apical membranes of enterocytes via several amino-acid transport systems (see Fig. 45-6). However, substantial amounts of protein are absorbed from the intestinal lumen as dipeptides, tripeptides, or tetrapeptides and then hydrolyzed to amino acids by intracellular peptidases.

The transporter responsible for the uptake of luminal oligopeptides (Fig. 45-8A) is distinct from the various amino-acid transporters. Furthermore, administering an amino acid as a peptide (e.g., the dipeptide glycylglycine) results in a higher blood level of the amino acid than administering an equivalent amount of the same amino acid as a monomer (e.g., glycine; see Fig. 45-8B). One possible explanation for this effect is that the oligopeptide cotransporter, which carries multiple amino acids rather than a single amino acid into the cell, may simply be more effective than amino-acid transporters in transferring amino-acid monomers into the cell. This accelerated peptide absorption has been referred to as a kinetic advantage and raises the question of the usefulness of the enteral administration of crystalline amino acids to patients with impaired intestinal function or catabolic deficiencies. The evidence for a specific transport process for dipeptides, tripeptides, and tetrapeptides comes from direct measurements of oligopeptide transport, molecular identification of the transporter, and studies of the hereditary disorders of amino-acid transport, cystinuria, and Hartnup disease.

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FIGURE 45-8 Absorption of oligopeptides. A, The H/oligopeptide cotransporter PepT1 moves dipeptides, tripeptides, and tetrapeptides into the enterocyte, across the apical membrane. Peptidases in the cytoplasm hydrolyze the oligopeptides into their constituent amino acids, which then exit across the basolateral membrane via one of three Na+-independent amino-acid transporters. B, If glycine is present in the lumen only as a free amino acid, then the enterocyte absorbs it only via apical amino-acid transporters. However, if the same amount of glycine is present in the lumen in the form of the dipeptide glycylglycine, the rate of appearance of glycine in the blood is about twice as high. Thus, PepT1, which moves several amino-acid monomers for each turnover of the transporter, is an effective mechanism for absorbing “amino acids.”

Oligopeptide uptake is an active process driven not by an Na+ gradient, but by a proton gradient. Oligopeptide uptake occurs via an H/oligopeptide cotransporter known as PepT1 (SLC15A1; see p. 123), which is also present in the renal proximal tubule. PepT1 also appears to be responsible for the intestinal uptake of certain dipeptide-like antibiotics (e.g., oral amino-substituted cephalosporins). As noted above, after their uptake, dipeptides, tripeptides, and tetrapeptides are usually hydrolyzed by cytoplasmic peptidases to their constituent amino acids, the forms in which they are transported out of the cell across the basolateral membrane. Because peptides are almost completely hydrolyzed to amino acids intracellularly, few peptides appear in the portal vein. Proline-containing dipeptides, which are relatively resistant to hydrolysis, are the primary peptides present in the circulation.

Amino acids enter enterocytes via one or more group-specific apical transporters

Multiple amino-acid transport systems have been identified and characterized in various nonepithelial cells. The absorption of amino acids across the small intestine requires sequential movement across both the apical and basolateral membranes of the villous epithelial cell. Although the amino-acid transport systems have overlapping affinities for various amino acids, the consensus is that at least seven distinct transport systems are present at the apical membrane (see Table 36-1); we discuss the basolateral amino-acid transporters in the next section. Whereas many apical amino-acid transporters are probably unique to epithelial cells, some of those at the basolateral membrane are probably the same as in nonepithelial cells.

The predominant apical amino-acid transport system is system B0 (SLC6A19, SLC6A15; see Table 36-1) and results in Na+-dependent uptake of neutral amino acids. As is the case for glucose uptake (see p. 919), uphill movement of neutral amino acids is driven by an inwardly directed Na+ gradient that is maintained by the basolateral Na-K pump. The uptake of amino acids by system B0 is an electrogenic process and represents another example of secondary active transport. It transports amino acids with an L-stereo configuration and an amino group in the α position. System B0+ (SLC6A14) is similar to system B0 but has broader substrate specificity. System b0+ (SLC7A9/SLC3A1 dimer) differs from B0+ mainly in being independent of Na+.

Other apical carrier-mediated transport mechanisms exist for anionic (i.e., acidic) α amino acids, cationic (i.e., basic) α amino acids, β amino acids, and imino acids (see Table 36-1). Because these transporters have overlapping affinities for amino acids, and because of species differences as well as segmental and developmental differences among the transporters, it has been difficult to establish a comprehensive model of apical membrane amino-acid transport in the mammalian small intestine (Box 45-3).

Box 45-3

Defects in Apical Amino-Acid Transport

Hartnup Disease and Cystinuria


Hartnup disease and cystinuria are hereditary disorders of amino-acid transport across the apical membrane. These autosomal recessive disorders are associated with both small-intestine and renal-tubule abnormalities (see Box 36-1) in the absorption of neutral amino acids in the case of Hartnup disease and of cationic (i.e., basic) amino acids and cystine in the case of cystinuria.

The clinical signs of Hartnup disease are most evident in children and include the skin changes of pellagra, cerebellar ataxia, and psychiatric abnormalities. In Hartnup disease, the absorption of neutral amino acids by system B0 (SLC6A19) in the small intestine is markedly reduced, whereas that of cationic amino acids is intact (Fig. 45-9).

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FIGURE 45-9 Genetic disorders of apical amino-acid transport. A, In Hartnup disease, an autosomal recessive disorder, the apical system B0 (SLC6A19) is defective. As a result, the absorption of neutral amino acids, such as L-phenylalanine, is reduced. However, the absorption of L-cystine (i.e., Cys-S-S-Cys) and cationic (i.e., basic) amino acids (e.g., L-arginine) remains intact. The enterocyte can absorb L-phenylalanine normally if the amino acid is present in the form of the dipeptide L-phenylalanyl-L-leucine, inasmuch as the oligopeptide cotransporter PepT1 is normal. B, In cystinuria, an autosomal recessive disorder, the apical system b0+ (SLC7A9/SLC3A1 dimer) is defective. As a result, the absorption of L-cystine and cationic amino acids (e.g., L-arginine) is reduced. However, the absorption of amino acids that use System B0 (e.g., L-alanine) is normal. The enterocyte can absorb L-arginine normally if the amino acid is present in the form of the dipeptide L-arginyl-L-leucine.

The principal manifestation of cystinuria is the formation of kidney stones. In cystinuria, the absorption of cationic amino acids by system b0+ (SLC7A9/SLC3A1 dimer) is abnormal as a result of mutations in SLC7A9 or SLC3A1, but absorption of neutral amino acids is normal.

Because neither of these diseases involves the oligopeptide cotransporter, the absorption of oligopeptides containing either neutral or cationic amino acids is normal in both diseases. Only 10% of patients with Hartnup disease have clinical evidence of protein deficiency (e.g., pellagra) commonly associated with defects in protein or amino-acid absorption. The lack of evidence of protein deficiency is a consequence of the presence of more than one transport system for different amino acids, as well as a separate transporter for oligopeptides. Thus, oligopeptides containing neutral amino acids are absorbed normally in Hartnup disease, and oligopeptides with cationic amino acids are absorbed normally in cystinuria.

These two genetic diseases also emphasize the existence of amino-acid transport mechanisms on the basolateral membrane that are distinct and separate from the apical amino-acid transporters. Thus, in both Hartnup disease and cystinuria, oligopeptides are transported normally across the apical membrane and are hydrolyzed to amino acids in the cytosol, and the resulting neutral and cationic amino acids are readily transported out of the cell across the basolateral membrane.

At the basolateral membrane, amino acids exit enterocytes via Na+-independent transporters and enter via Na+-dependent transporters

Amino acids appear in the cytosol of intestinal villous cells as the result either of their uptake across the apical membrane or of the hydrolysis of oligopeptides that had entered the apical membrane (see Fig. 45-6). The enterocyte subsequently uses ~10% of the absorbed amino acids for intracellular protein synthesis.

Movement of amino acids across the basolateral membrane is bidirectional; the movement of any one amino acid can occur via one or more amino-acid transporters. At least six amino-acid transport systems are present in the basolateral membrane (see Table 36-1). Three amino-acid transport processes on the basolateral membrane mediate amino-acid exit from the cell into the blood and thus complete the process of protein assimilation. Two other amino-acid transporters mediate uptake from the blood for the purposes of cell nutrition. The three Na+-independent amino-acid transport systems appear to mediate amino-acid movement out of the epithelial cell into blood. The two Na+-dependent processes facilitate their movement into the epithelial cell. Indeed, these two Na+-dependent transporters resemble those that are also present in nonpolar cells.

In general, the amino acids incorporated into protein within villous cells are derived more from those that enter across the apical membrane than from those that enter across the basolateral membrane. In contrast, epithelial cells in the intestinal crypt derive almost all their amino acids for protein synthesis from the circulation; crypt cells do not take up amino acids across their apical membrane (Box 45-4).

Box 45-4

Defect in Basolateral Amino-Acid Transport

Lysinuric Protein Intolerance


Lysinuric protein intolerance is a rare autosomal recessive disorder of amino-acid transport across the basolateral membrane (Fig. 45-10). Evidence indicates impaired cationic amino-acid transport, and symptoms of malnutrition are seen. It appears that the defect is in system y+L, which is located solely on the basolateral membrane. System y+L has two subtypes, y+LAT1 (SLC7A7/SLC3A2 dimer) and y+LAT2 (SLC7A6/SLC3A2 dimer). Mutations in the SLC7A7 gene (subtype y+LAT1) cause the disease lysinuric protein intolerance. These patients exhibit normal absorption of cationic amino acids across the apical membrane. Unlike in Hartnup disease or cystinuria, in which the enterocytes can absorb the amino acid normally if it is presented as an oligopeptide, in lysinuric protein intolerance the enterocytes cannot absorb the amino acid regardless of whether the amino acid is “free” or is part of an oligopeptide. These observations are best explained by hypothesizing that the patients hydrolyze intracellular oligopeptides properly but have a defect in the transport of cationic amino acids across the basolateral membrane. This defect is present not only in the small intestine but also in hepatocytes and kidney cells, and perhaps in nonepithelial cells as well.

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FIGURE 45-10 Genetic disorder of basolateral amino-acid transport. Lysinuric protein intolerance is an autosomal recessive defect in which the Na+-independent y+L amino-acid transporter on the apical and basolateral membranes is defective. However, the absence of apical y+L (SLC7A6/SLC3A2 or SLC7A7/SLC3A2 dimers) does not present a problem because Na+-dependent amino-acid transporters can take up lysine, and PepT1 can take up lysine-containing oligopeptides (Lys-XX). However, there is no other mechanism for moving lysine out of the enterocyte across the basolateral membrane.

 

SMALL INTESTINE

LARGE INTESTINE

Length (m)

6

2.4

Area of apical plasma membrane (m2)

~200

~25

Folds

Yes

Yes

Villi

Yes

No

Crypts or glands

Yes

Yes

Microvilli

Yes

Yes

Nutrient absorption

Yes

No

Active Na+ absorption

Yes

Yes

Active K+ secretion

No

Yes