Molecular mechanisms of nutrient transport

Paracellular diffusion: Water, some inorganic ions, and a lew other very small compounds can bypass the intestinal cells altogether by traveling (in either direction) through very narrow (4-XA) pores of the tight junctions sealing lite spaces between enterocytes. The tight junctions of the proximal small intestine consist of fewer strands of sealing proteins w ith pore sizes of about 8 A and are therefore more permeable than distal intestinal segments with tight junction pore sizes of only 4 A.

Active ATP-driven transport: Several ATP-hydrolyzing complexes transport nutrients across luminal, intracellular, and basolateral membranes. Crossing intracellular membranes is often necessary to mov e molecules out of endosomes lysosomes. across the inner mitochondrial membrane or into secretory compartments. There is a group of nearly fifty ATP-binding cassette transporters (ABC transporters) that use the energy from ATP hydrolysis to move medium-sized molecules across membranes or to adjust their shape for regulatory purposes. Several are critical for intestinal absorption, such as CFTR (ABCC7) for the regulation of chloride secretion, the ABC transporters AI and G5 08 for the control of cholesterol absorption efficiency, and multidrug resistance protein 2 (MRP2: ABCC2) for folate export across the basolateral membrane.

Then there are highly specialized ATPases for the absorption of copper and calcium. Menkes protein (ATP7A: EC3,6.3.4) transports copper into secretory vesiclcs for export into blood. The calcium-transporting ATPase lb (plasma membrane calcium-pumping ATPase lb. PMCAlb; EC3.6.3.8) moves calcium directly across the basolateral membrane.

The ATPases that pump sodium and potassium do the really heavy lifting in nutrient absorption. The sodium potassium-exchanging ATPase (EC3.6.3.9) labors at the basolateral membrane of all enterocytes throughout the small and large intestines. Each ATP-hydrolyzing cycle pumps three sodium ions out of the cell into basolateral space and pulls in two potassium ions in exchange. This establishes the low intracellular sodium concentration (Zuidcma et al., 1986) that is the main driving force for active nutrient transport.

Sodium cotransport; Specific transporters use the electrochemical potential by firmly coupling the movement of the nutrient ligand to that of sodium along the steep sodium gradient. Examples for sodium-driven bulk transporters arc the sodium-glucose transporter 1 (SLC2A2) and the amino acid transport system B' (ASCT2, SLCIA5), which every day move several hundred grams of nutrients plus several liters of water out of the small intestinal lumen. It should be noted that similar cotransporters al the basolateral membrane allow postprandial nutrient (lux from the enterocytes towards the blood capillaries, and also in the opposite direction during fasting, to supply nutrients for the enierocyte's own considerable needs.

Proton cotranspori: The sodium hydrogen exchanger 3 (NHE3. SLC9A3)at the luminal side and the sodium/hydrogen exchanger 2 (NHE2. SLC9A2) at the basolateral side move protons out of the enterocytes and establish a significant proton gradient. Hydrogen ions (protons) can then drive nutrient cotransport just like sodium ions do. Examples of proton-driven transporters are the monocarboxylic acid transporter I (MCTI. SLC16AI) for lactate, pyruvate, acetate, propionate, benzoatc. and nicotinate

Nutrient Uptake Mechanism

membrane membrane endothelium

Figure 4.2 The sodium gradient established by sodium-potassium ATPase drives nutrient transport from the intestinal lumen into cnterocyrcs membrane membrane endothelium

Figure 4.2 The sodium gradient established by sodium-potassium ATPase drives nutrient transport from the intestinal lumen into cnterocyrcs

(Orsenigo et a!.. 1999) and the hydrogen ton peptide eotransporter I (PepTl. SLC15A1 ).

Chloride cotransport: The taurine transporter (TAUT, SLC6A6) uses the chloride gradient in the ileum for the uptake of taurine from bile acids. Exchangers: Some transporters function in such a way that a mass gradient pushes another type of molecule in the opposite direction. The above-mentioned sodium-hydrogen exchangers, for instance, use the gradient-driven inward movement of sodium to push protons out of the cell. Another example is the putative anion transporter I ( PAT I. SLC26A6) in the proximal small intestine, which very effectively couples the recovery of chloride with the countertransport of bicarbonate for neutralizing gastric (hydrochloric) acid. A group of membrane-anchored glycoproteins at both sides of the enterocytes uses neutral amino acids to move other amino acids in the opposite direction. This means thai alanine (or another neutral amino acid consumed in bulk), whose intracellular concentration increases añera meal due to uptake v ia the sodium-driven transport system B°, moves back into the intestinal lumen to drive cystine (oxidized cysteine) into the cell. The alanine is then, of course, taken up again via system B°,

Facilitated diffusion: Several transporters mediate the selective transfer of nutrients along their concentration gradient. Important examples are the transporter for fructose (GLUT5. SLC2A5) on the luminal side ol'thc proximal small intestine, and the glucose transporter 2 (til I IT2, SLC3A2) at the basolateral side. GLUT2 also serves nutritive functions for enterocytes as mentioned above for the sodium-driven amino aeid transporters.

intracellular transformation. Phosphorylation or other chemical changes commonly take place after the uptake of nutrients to prevent them from returning into the intestinal lumen by the way they entered. The absorption of vitamin 136 pro\ ides an example for such "trapping." The pyridoxin carrier accepts only free pyridoxin, and conversion to pyridoxin phosphate keeps the equilibrium always in fa\or of the influx direction.

Nutrients also are metabolized to pro\ ide energy and material for the needs of the rapidly proliferating intestinal cells. Glutamine, for example, is a major energy fuel as well as nitrogen source for the intestines. Some glutamine in enterocytes is also used for the synthesis of ornithine and citruiline. which is exported for use in the urea cycle of liver and kidneys and for the arginine synthesis. Thus, only some of the absorbed glutamine reaches blood circulation.

Unmediated transcellufor diffusion: Very few compounds can dircctly cross the formidable barrier of the bilayer membranes on the apical and basolateral sides of the cells lining the intestinal lumen. These arc mainly smalt lipophilic compounds, urea and gases (hydrogen, methane, hydrogen sullidei.

Transcytosis: The brush border membrane folds in and connects to vesicular structures of the endosomal compartment that also prov ides a secretory pathway on the basolateral side. This endosomal mechanism can transport intestinal peptide hormones as well as small amounts of ingested proteins and peptides (Ziv and Bendayan. 2000). Transcytosis explains how cow milk protein or gluten can evade intracellular catabolism.

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