Why is a fluid environment necessary for digestion of nutrients?
It allows for contact of enzymes with food particles, diffusion of digested nutrients to absorption sites, and transit of nutrients along the GI tract without damaging the epithelium.
Where is most water absorbed?
More total water is absorbed in the small intestine, but the colon is more efficient and absorbs a larger percentage of the water that passes through.
How does water flow?
It follows osmotic gradients established by active transport.
What is claudin?
A tight junction protein that acts as a "seal" for large molecules and forms aqueous pores permeable to Na+ and Cl-
Where do aquaporins play a role in GI water transport?
Salivary glands, hepatocytes, and possibly the intestine
What is the type of transport for ethanol absorption?
What is the type of transport for epithelial Na+ channel?
What is the type of transport for Na+/K+ ATPase?
Primary active transport
What is the type of transport for Na+/Glucose cotransporter?
Secondary active transport
What is the type of transport for glucose transporter?
What is the type of transport for Na+/H+ exchanger?
Secondary active transport
How is transport rate determined?
Transport rate = area x flux
What determines osmolarity and volume in the duodenum?
Osmolarity and volume of contents are dominated by water movement (which is determined by the osmolarity of the chyme).
What determines osmolarity and volume in the small intestine?
Osmolarity and volume of contents are determined by both water and solute movement. Water is moved by the osmotic force created by actively transported electrolytes.
What happens when a hypotonic fluid reaches the duodenum?
The lumen of the duodenum becomes hypotonic and water is moved into blood.
What happens when a hypertonic fluid reaches the duodenum?
The lumen of the duodenum becomes hypertonic and water is moved from blood to the lumen while Na+ and Cl- are transported from the lumen into the blood.
What is dumping syndrome?
After some gastric surgeries, there is an abnormally rapid and large delivery of hypertonic gastric contents into the small intestine. Intravascular fluid moves into the lumen, leading to tachycardia, palpitations, diarrhea, cramps, and bloating.
What creates the standing osmotic gradient in the intestines?
Active transport of Na+ by Na+/K+ ATPase increases the osmolarity of the lateral intercellular space and creates positice potential outside, so Cl- diffuses out passively along its electrochemical gradient.
What are the 4 ways Na+ can enter the small intestine epithelial cell?
1) passively through membrane channels
2) cotransport with nutrients such as glucose and amino acids
3) cotransport with Cl-
4) countertransport with H+
What are the steps in coupled transport of Na+ and glucose?
1) an inward EC gradient for Na+ is established
2) SGLT-1 co-transports Na+ downhill while moving glucose uphill thanks to secondary active transport
3) SGLT-1 also transports ~300 H2O molecules
4) glucose exits ward the blood via the GLUT-2 carrier by facilitated diffusion
What do crypt cells do?
They maintain liquid chyme through transcellular secretion of Cl- that drives Na+ and water secretion.
What does cholera toxin do?
It causes secretory diarrhea. The A subunit of the enterotoxin activates continuous production of cAMP, which activates the CFTR and increases secretion (loss) of Cl-, Na+, and water.
How does rotavirus cause secretory diarrhea?
It decreases absorption of Na+ and Cl- via the cotransporter, but SGLT1 is relatively spared. This is important because less glucose and Na+ is needed to rehydrate in non-cholera diarrhea.
What are the 3 mechanisms by which Cl- can enter the small intestine epithelial cell?
1) cotransport with Na+
2) countertransport with HCO3-
3) paracellular pathway, which is passive
How is Na+ absorbed in the colon?
It enters the cell via ENaC and exits the basolateral membrane via Na+/K+ pump
How is K+ movement different in the colon than in the small intestine?
In the small intestine there is net absorption via paracellular pathways. In the colon, secretion can occur because the cell membrane is more permeable to K+ thansk to channels.
What role does aldosterone have in the colon?
It stimulates Na+ absorption and K+ secretion
What are the types of Ca2+ transport in the small intestine?
There is paracellular transport when intake is high and transcellular transport when intake is low. It must cross enterocytes without killing them; intracellular [Ca2+] above several uM is extremely cytotoxic.
How is Ca2+ absorbed?
1) entry via channels
2) intracellular diffusion bound to CaBP to keep free volume low and uptake into organelles
3) extrusion via CaATPase or Na+/Ca2+ exchanger
The expression of all carriers is upregulated by 1.25-dihydroxy-vitamin D3
What happens in respnse to a decrease in serum Ca2+?
PTH secretion increases as well as 1,25-OH-D3. Intestinal vitamin D receptor (VDR) is activates and there is increased absorption of Ca2+
How is heme iron absorbed?
There is uptake by endocytosis, then Fe2+ is released by heme oxygenase
How is non-heme iron absorbed?
It is first reduced from Fe3+ to Fe2+ and then transported by the divalent metal transporter.
What factors reduce Fe3+ to Fe2+ and therefore increase the absorption of iron?
Duodenal cytochrome B on the apical membrane
What is the divalent metal transporter (DMT)?
It cotransports Fe2+ with H+ on the apical membrane along the inward gradient for H+ established by a Na+/H+ exchanger on the apical membrane.
What happens to iron inside the enterocyte?
Regardless of the source, it resides in a common pool. Part of the iron binds to Ferritin because free iron is toxic. Each ferritin molecule can bind ~4500 atoms of iron, moch of which is lost when the cell exfoliates. More ferritin is formed when body iron stores are high.
How does iron leave the cell?
Fe2+ is transported out through the basolateral membrane by Ferroportin, then is oxidized to Fe3+ by hephaestin, a membrane-bound ferroxidase. Plasma transferrin carries 2Fe3+ throughout the body.
What regulates iron absorption?
The hormone hepcidin inhibits iron transport from enterocyte to blood by decreasing ferroportin. Secretion of hepcidin increases during iron overload and decreases during iron deficiency.
What is a major difference between carbohydrates/proteins and lipids?
Carbs and proteins are hydrophilic and transport across the enterocyte is a much bigger problem than solubilization in the lumen. Lipids are hydrophobic so solubilization is a bigger problem than transport.
What differences are there between carbohydrate and protein absorption?
Protein assimilation has a broader spectrum of transporters and can be transported as amino acids, di-, and tripeptides (compared to monosaccharides only). Peptides also require a final stage of digestion into amino acids in the cytosol.
Where is the largest portion of sugar absorption?
Mid small intestine
Where is the largest portion of amino acid absorption?
Equally along the small intestine
Where is the largest portion of long chain fatty acid absorption and conversion to triglyceride?
Upper small intestine
Where is the largest portion of bile acids absorption?
Lower small intestine and colon
What does SGLT1 transport?
Galactose and glucose from the lumen into the enterocyte
What does GLUT5 transport?
Fructose from the lumen into the enterocyte
What does GLUT2 transport?
Galactose from the enterocyte into the capillary
What genetic mutation underlies glucose-galactose malabsorption?
A missense mutation in SGLT1
What happens in glucose-galactose malabsorption?
Neither glucose nor galactose is transported, leading to severe osmotic diarrhea at birth and if left untreated. Glucose, galactose and lactose must be removed from the diet, and fructose can be used to meet energy requirements. (There is no glycosuria because SGLT2 in the kidneys is not affected)
What does PEPT1 transport?
Di- and tripeptides
How do amino acids enter the enterocyte?
Na+ dependent or independent amino acid transporters
How are di- and tripeptides absorobed?
1) An inward-directed H+ gradient is created by Na+/H+ exchanger
2) Cotransport of peptides with H+ utilizes the inward electrochemical gradient for H+
3) Hydrolysis by intracellular peptidases to AA
4) AA exits basolateral membrane to portal blood via AA carriers
What are the general properties of amino acid transporters?
They exist on apical and basolateral membranes, are stereospecific but have broad substrate specificity and overlapping specificity, and there are multiple transport systems for neutral, cationic, and anionic AAs.
Why is it relevant that there are separate pathways for amino acid and peptide reabsorption?
Patients with genetic defects of AA absorption do not experience protein malnutrition because the amino acids can still be received from peptides, as is the case in cystinuria and Hartnup disease.
Why are peptides better to have around than amino acids?
They allow more efficient absorption by PEPT1 compared to AAs and reduce the tonicity of the solution.
How are monoglycerides, free fatty acids, and bile salts moved into the enterocytes?
Emulsion droplets are mixed with bile salts to form mixed micelles, which move down into the microvilli to allow their contents to enter the cells without receptors.
What are long chain triglycerides?
They are made up of a glycerol esterified with 3 FA, with > 12 carbons. They are a major source of lipid in the diet and the major form of stored energy in the body.
What processes are required for lipid absorption?
1. Generation of lipid emulsion
2. Hydrolysis to monoglycerides and free fatty acids
3. Formation of micelles
4. Diffusion of MG and FA through lipid bilayer
5. Resynthesis of triglycerides in epithelial cell
6. Formation of chylomicrons
7. Exocytosis of chylomicrons
8. Transfer to lymphatics, capillaries.
What happens to lipids in the stomach?
Fat emulsions are destabilized by the acidic pH to form a "cream layer." Stomach contractions create mixing vortexes that break them into smaller droplets. High shearing forces in the antrum/pylorus area further decrease droplet size to increase surface area. Gastric and salivary lipase begin lipolysis but nos fat arrives in the duodenum intact.
What are micelles?
Small aggregates of mixed lipids and bile acids suspended in the intestinal fluid. They are composed of bile salts, phospholipids (lecithin), monoglycerides, [long chain] fatty acids, and cholesterol.
How are micelles different from emulsified lipid droplets?
They form a true solution
What is the critical micellar concentration?
The concentration of bile salts at which molecular aggregation occurs.
What is unique to lipid assimilation?
Reassembly and packaging
What are the main anions in stool?
Short-chain fatty acids
What is the rate-limiting step for lipid assimilation?
Micelles must reach the enterocyte membrane and diffuse across the unstirred layer
How do long chain fatty acids cross the membrane?
They must become protonated to become soluble and cross the membrane by simple diffusion and some carrier proteins.
How do medium chain and long chain fatty acids differ in absorption?
Medium chain FAs are water-soluble and less reliant on bile salts, so they can be transported directly into portal blood without chylomicrons.
What are chylomicrons?
Apolipoproteins with a lipid core used to transport long chain FAs into the lymph by vesicular exocytosis. They are too large to cross the basement membrane surrounding capillaries.
How is cholesterol absorbed?
1. Uptake from lumen via a protein carrier NPC1L1
2. Some export to lumen via an ATP-consuming pump
3. Utilized within the enterocyte
4. Incorporation into chylomicrons
What happens to circulating bile salts?
95% are reabsorbed into blood by Na+-dependent active transport only in distal ileum or passive diffusion in the small intestine and colon, then returned to the liver via portal circulation for re-secretion. 5% are lost in feces, which is matched by hepatic synthesis.
What parts of the GI correlate with lipolysis, micellar solubilization with bile acid, absorption, and delivery?
Micellar solubilization with bile acid: liver/ileum
Absorption: Jejunal mucosa