Digestion and Absorption

Absorption of lipids • Absorption of lipids occurs in a series of steps illustrated in Figure 39 and is described as follows: ?

1. The products of lipid digestion (cholesterol, monoglycerides, lysolecithin, and free fatty acids) are solubilized in the intestinal lumen in mixed micelles, except glycerol, which is water soluble. The hydrophilic portion of the bile salt molecules dissolves in the aqueous solution of the intestinal lumen, thus solubilizing the lipids in the micellar core. 2. The micelles diffuse to the apical membrane of the intestinal epithelial cells. The lipids are released from the micelle and diffuse down their concentration gradients into the cell. The micelles per se do not enter the cell, however, and the bile salts are left behind in the intestinal lumen to be absorbed downstream in the ileum. 3. Inside the intestinal epithelial cells, the products of lipid digestion are re- esterified with free fatty acids on the smooth endoplasmic reticulum to form the original ingested lipids, triglycerides, cholesterol ester, and phospholipids. 4. Inside the cells, the re-esterified lipids are packaged with apoproteins in lipid- carrying particles called chylomicrons which are composed of triglycerides and cholesterol at the core and phospholipids and apoproteins on the outside. Phospholipids cover 80% of the outside of the chylomicron surface, and the remaining 20% of the surface is covered with apoproteins. Apoproteins, which are synthesized by the intestinal epithelial cells, are essential for the absorption of chylomicrons. 5. The chylomicrons are packaged in secretory vesicles on the Golgi apparatus. The secretory vesicles migrate to the basolateral membranes, and there is exocytosis of the chylomicrons. The chylomicrons are too large to enter vascular capillaries, but they can enter the lymphatic capillaries (lacteals) by moving between the endothelial cells that line the lacteals. The lymphatic circulation carries the chylomicrons to the thoracic duct, which empties into the bloodstream.

Absorption of other substances Vitamins • Vitamins are required in small amounts to act as coenzymes or cofactors for various metabolic reactions. Because vitamins are not synthesized in the body, they must be acquired from the diet and absorbed by the GI tract. • Categorized as either fat soluble or water soluble. FatSolubleVitamins Vitamins ?. The mechanism of absorption of fat-soluble vitamins is the same as that for the dietary lipids: ?

A, D, E, and K fat- soluble vitamins are incorporated into micelles and transported to the apical membrane of the intestinal cells, diffuse across the apical membrane into the cells, are incorporated in chylomicrons, and then are extruded into lymph, which delivers them to the general circulation.

c) Iron • Iron is absorbed across ? • Free iron binds to ? In the circulation, ?

the apical membrane of intestinal epithelial cells as free iron (Fe2+) or as heme iron (i.e., iron bound to hemoglobin or myoglobin). apoferritin and is transported across the basolateral membrane into the blood. iron is bound to a β- globulin called transferrin, which transports it from the small intestine to storage sites in the liver. From the liver, iron is transported to the bone marrow, where it is released and utilized in the synthesis of hemoglobin.

(3) Lipids • The dietary lipids include ? A factor that greatly complicates lipid digestion and absorption is their ? (a) Digestion of lipids • The digestion of dietary lipids begins in the stomach with the action of ?

triglycerides, cholesterol, and phospholipids. insolubility in water (their hydrophobicity). Because the GI tract is filled with an aqueous fluid, the lipids must somehow be solubilized to be digested and absorbed. lingual and gastric lipases and is completed in the small intestine with the actions of the pancreatic enzymes pancreatic lipase, cholesterol ester hydrolase, and phospholipase A2 (Fig. 38).

•Small Intestine- lipid absorption and breakdown What is secreted into the sm intestine to perform this work? • Pancreatic lipase is secreted as ? A potential problem in the action of pancreatic lipase is ? CE? PA2? • The final products of lipid digestion are ?. With the exception of glycerol, each end product is ?

• Bile salts are secreted into the lumen of small intestine, that together with lysolecithin and products of lipid digestion, surround and emulsify dietary lipids. The pancreatic enzymes (pancreatic lipase, cholesterol ester hydrolase, and phospholipase A2) and one special protein (colipase) are secreted into the small intestine to accomplish the digestive work (Fig. 38). the active enzyme. It hydrolyzes triglyceride molecules to one molecule of monoglyceride and two molecules of fatty acid. that it is inactivated by bile salts. This is why colipase is secreted in pancreatic juices in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Colipase then displaces bile salts at the lipid-water interface and binds to pancreatic lipase. With the inhibitory bile salts displaced, pancreatic lipase can proceed with its digestive functions. • Cholesterol ester hydrolase is secreted as an active enzyme and hydrolyzes cholesterol ester to free cholesterol and fatty acids. It also hydrolyzes ester linkages of triglycerides, yielding glycerol. • Phospholipase A2 is secreted as a proenzyme and, like many other pancreatic enzymes, is activated by trypsin. Phospholipase A2 hydrolyzes phospholipids to lysolecithin and fatty acids. monoglycerides, fatty acids, cholesterol, lysolecithin, and glycerol (from hydrolysis of ester bonds of triglycerides) hydrophobic and therefore is not soluble in water. Now the hydrophobic digestive products must be solubilized in micelles and transported to the apical membrane of the intestinal cells for absorption.

Water Soluble Vitamins • Vitamins B1, B2, B6, B12, C, biotin, folic acid, nicotinic acid, and pantothenic acid. In most cases, absorption of the water-soluble vitamins occurs via an ? • The exception is the absorption of vitamin B12 (cobalamin) (Fig. 41). Absorption of vitamin B12 requires intrinsic factor and occurs in the following steps:? • A consequence of gastrectomy is ?

Na+-dependent cotransport mechanism in the small intestine. (1)Dietary vitamin B12 is released from foods by the digestive action of pepsin in the stomach. (2) Free vitamin B12 binds to R proteins, which are secreted in salivary juices. (3) In the duodenum, pancreatic proteases degrade the R proteins, causing vitamin B12 to be transferred to intrinsic factor, a glycoprotein secreted by the gastric parietal cells. (4) The vitamin B12-intrinsic factor complex is resistant to the degradative actions of pancreatic proteases and travels to the ileum, where there is a specific transport mechanism for its absorption. loss of the source of intrinsic factor, the parietal cells. Therefore, after a gastrectomy, patients fail to absorb vitamin B12 from the ileum, eventually become vitamin B12 deficient, and may develop pernicious anemia. To prevent pernicious anemia, vitamin B12 must be administered by injection; orally supplemented vitamin B12 cannot be absorbed in the absence of intrinsic factor.

(a) Intestinal absorption Intestinal epithelial cells lining the villi absorb large volumes of fluid. The first step in this process is the ? followed by ?

absorption of solute, followed by the absorption of water. The solute absorptive mechanisms vary among the jejunum, the ileum, and the colon.

(b) Absorption of carbohydrates • Glucose and galactose are absorbed by ? • Glucose and galactose are extruded ? • Fructose is handled differently from glucose and galactose. ?

across the apical membrane by secondary active transport mechanisms. from the cell into the blood, across the basolateral membrane, by facilitated diffusion (GLUT 2) (Fig. 34). Fructose is transported across both the apical and basolateral membranes by facilitated diffusion: in the apical membrane, via the fructose- specific transporter is called GLUT 5, and in the basolateral membrane, via GLUT 2 (Fig. 34).

(b) Absorption of proteins • The products of protein digestion are ?. Each form can be absorbed by intestinal epithelial cells. • The L-amino acids are absorbed by ? • Most ingested protein is absorbed by ?

amino acids, dipeptides, and tripeptides mechanisms analogous to those for monosaccharide absorption. The amino acids are transported from the lumen into the cell by Na+−amino acid cotransporters in the apical membrane, energized by the Na+ gradient (Fig.37). There are four separate cotransporters: one each for neutral, acidic, basic, and imino amino acids. The amino acids then are transported across the basolateral membrane into the blood by facilitated diffusion, again by separate mechanisms for neutral, acidic, basic, and imino amino acids. intestinal epithelial cells in the dipeptide and tripeptide forms rather than as free amino acids. Inside the cell, most of the dipeptides and tripeptides are hydrolyzed to amino acids by cytosolic peptidases, producing amino acids that exit the cell by facilitated diffusion; the remaining dipeptides and tripeptides are absorbed unchanged (Fig. 37).

(2) Proteins • Dietary proteins are digested to absorbable forms, which include ? by what? what else is similarly absorbed? (a) Digestion of proteins • The digestion of protein begins ? and is completed in ? The two classes of proteases are ? and ? • Endopeptidases ? Exopeptidases ?

amino acids, dipeptides, and tripeptides, by proteases in the stomach and small intestine and then absorbed into the blood. The proteins contained in GI secretions (e.g., pancreatic enzymes) are similarly digested and absorbed. in the stomach with the action of pepsin, the small intestine with pancreatic and brush-border proteases (Fig. 35). endopeptidases and exopeptidases. hydrolyze the interior peptide bonds of proteins. The endopeptidases of the GI tract are pepsin, trypsin, chymotrypsin, and elastase. hydrolyze one amino acid at a time from the C- proteins and peptides. The exopeptidases of the gastrointestinal tract are carboxypeptidases A and B.

• Structural features of the intestinal mucosa ? • The length of the villi ? The surfaces of the villi are lined with ? • The apical surface of the epithelial cells is further expanded by ?

called villi and microvilli increase the surface area of the small intestine, maximizing the exposure of nutrients to digestive enzymes and creating a large absorptive surface. The surface of the small intestine is arranged in longitudinal folds, called folds of Kerckring. Fingerlike villi project from these folds. decreases from the duodenum (where most digestion and absorption occurs), to the terminal ileum. epithelial cells (enterocytes) interspersed with mucus-secreting cells (goblet cells). tiny enfoldings called microvilli, which is collectively called the brush border because of its "brushlike" appearance under light microscopy. Together, the folds of Kerckring, the villi, and the microvilli increase total surface area by 600-fold.

• The beginning of protein digestion occurs in the stomach (Fig. 36, A), via? pH? • Protein digestion continues in the small intestine (Fig. 36, B) with the combined actions of pancreatic and brush-border proteases. Five major pancreatic proteases are secreted as inactive precursors: ? How does the activation of these work?

pepsin. There are three isozymes of pepsin, each of which has a pH optimum ranging between pH 1 and 3; above pH 5, pepsin is denatured and inactivated. trypsinogen,chymotrypsinogen, proelastase, procarboxypeptidase A, and procarboxypeptidase B. • First, trypsinogen is activated to trypsin by the brush-border enzyme enterokinase (Fig. 36, B). Initially, a small amount of trypsin is produced, which then catalyzes the conversion of all of the other inactive precursors to their active enzymes (including its own). The activation steps yield five active enzymes for protein digestion: trypsin, chymotrypsin, elastase, carboxypeptidase A, and carboxypeptidase B that digest all proteins to the absorbable units. Finally, the pancreatic proteases digest themselves and each other.

(1) Carbohydrates • Ingested carbohydrates are? (a) Digestion of carbohydrates • Only are absorbed? • Digestion of starch begins with ? • Pancreatic amylase digests ? • The three disaccharides in food are ?

polysaccharides, disaccharides (sucrose, lactose, maltose, and trehalose), and small amounts of monosaccharides (glucose and fructose). monosaccharides are absorbed by the intestinal epithelial cells, so all ingested carbohydrates must be digested to monosaccharides: glucose, galactose, or fructose. salivary α-amylase in the mouth; it is however inactivated by the low pH of the gastric contents. interior 1,4-glycosidic bonds in starch, yielding three disaccharides, α-limit dextrins, maltose, and maltotriose. These disaccharides are further digested to monosaccharides by the intestinal brush-border enzymes, α-dextrinase, maltase, and sucrase. The product of each of these final digestive steps is glucose. trehalose, lactose, and sucrose. Each molecule of disaccharide is digested to two molecules of monosaccharide by the enzymes trehalase, lactase, and sucrose (Fig. 33). Thus, the three possible end products of carbohydrate digestion are: glucose, galactose, and fructose.

Colon- absorption ?

The apical membrane contains Na+ and K+ channels, which are responsible for Na+ absorption and K+ secretion. Synthesis of the Na+ channels is induced by aldosterone, which + leads to increases in Na absorption and, secondarily, to increases in K+ secretion (Fig. 44). Increased number of Na+ channel leads to increased Na+ entry across the apical membrane and increased Na+ pumped out across the basolateral + + membrane by the Na -K ATPase, which leads to increased K pumped into the cell, and, finally, increased K+ secretion across the apical membrane. In diarrhea, the high flow rate of intestinal fluid causes increased colonic K+ secretion, resulting in increased K+ loss in feces and hypokalemia.

c) Malabsorption of lipids-steatorrhea Pancreatic insufficiency. ? Deficiency of bile salts - ? Bacterial overgrowth - ? Abetalipoproteinemia - ?

Diseases of the exocrine pancreas (e.g., chronic pancreatitis and cystic fibrosis) result in failure to secrete adequate amounts of pancreatic enzymes including those involved in lipid digestion, pancreatic lipase and colipase, cholesterol ester hydrolase, and phospholipase A2. interferes with the ability to form micelles, which are necessary for solubilization of the products of lipid digestion. Ileal resection (removal of the ileum) interrupts the enterohepatic circulation of bile salts, which then are excreted in feces rather than being returned to the liver. Because the synthesis of new bile salts cannot keep pace with the fecal loss, the total bile salt pool is reduced. reduces the effectiveness of bile salts by de-conjugating them. At intestinal pH, bile acids are primarily in the non-ionized form, which is lipid soluble, and readily absorbed by diffusion across the intestinal epithelial cells. For this reason, the bile acids are absorbed "too early" (before reaching the ileum), before micelle formation and lipid absorption is completed. Similarly, decreased pH in the intestinal lumen promotes "early" absorption of bile acids by converting them to their non-ionized form. failure to synthesize Apo B (β-lipoprotein). In this disease, chylomicrons either do not form or are unable to be transported out of intestinal cells into lymph. In either case, there is decreased absorption of lipids into blood and a buildup of lipid within the intestinal cells.

Jejunum- absorption • ?

The jejunum is the major site for Na+ absorption in the small intestine (Fig. 43, A). Na+ enters the epithelial cells of the jejunum via several different Na+-dependent coupled transporters. The apical membrane contains Na+-monosaccharide + cotransporters (Na+- glucose and+ Na- galactose), Na −amino acid cotransporters, and Na+-H+ exchanger. After Na+ enters the cell on the coupled transporters, it is extruded across the basolateral membrane via the Na+-K+ ATPase. Note that the source of H+ for Na+-H+ exchange is intracellular CO2 and H2O, which are converted to H+ and HCO3−.

(c) Clinical disorders of carbohydrate absorption - Osmotic diarrhea ? Lactose intolerance, ?

The most common culprit for disorders of carbohydrate absorption is the inability to break down ingested carbohydrates to an absorbable form (i.e., to monosaccharides). When non-absorbable carbohydrates remain in the GI lumen, they associate with an equivalent amount of water to keep the intestinal contents isosmotic. Retention of this solute and water in the intestine causes osmotic diarrhea. which is caused by lactase deficiency in the brush-border and lactose is not digested to glucose and galactose. Lactose holds water in the lumen, and causes osmotic diarrhea.

Disorders of protein digestion and absorption: Disorders of protein digestion or absorption occur when there is a ? In disorders of the exocrine pancreas ? The absence of trypsin alone makes it appear as if ? Several diseases are caused by a defect in or absence of a ? Cystinuria is a genetic disorder in which the ?

deficiency of pancreatic enzymes or when there is a defect in the transporters of the intestinal epithelial cells. such as chronic pancreatitis and cystic fibrosis, there is a deficiency of all pancreatic enzymes including the proteases. Dietary protein cannot be absorbed if it is not digested by proteases to amino acids, dipeptides, and tripeptides. all of the pancreatic enzymes are missing because trypsin is necessary for the activation of all precursor enzymes (including trypsin itself) to their active forms. Na+ −amino acid cotransporter. transporter for the dibasic amino acids cystine, lysine, arginine, and ornithine is absent in both the small intestine and the kidney. Consequently, none of these amino acids is absorbed by the intestine or reabsorbed by the kidney. The intestinal defect results in failure to absorb the amino acids, which are excreted in feces. The renal defect results in increased excretion of these specific amino acids and gives the disease its name, cystinuria or excess cystine excretion.

• Stomach: • Churns and mixes dietary lipids and initiates ? Enzymes involved? • One of the most important contributions of the stomach to overall lipid digestion (and absorption) is that it ?

enzymatic digestion. The churning action breaks the lipids into small droplets, increasing the surface area for digestive enzymes. In the stomach, the lipid droplets are emulsified by dietary proteins. • Lingual and gastric lipases initiate lipid digestion by hydrolyzing approximately 10% of ingested triglycerides to glycerol and free fatty acids (Fig. 38). empties chyme slowly into the small intestine, allowing adequate time for pancreatic enzymes to digest lipids. The rate of gastric emptying, which is so critical for subsequent intestinal digestive and absorptive steps, is slowed by CCK. CCK is secreted when dietary lipids first appear in the small intestine.

Intestinal fluid and electrolyte transport • Together, the small and large intestines absorb approximately 8.5 L of fluid daily, an amount almost equal to the entire extracellular fluid volume (Fig. 42) • Of this 9 L, most is absorbed by the ?. The small remaining volume that is not absorbed (~ 100 mL) is ? • The small intestine and colon not only absorb ? • The mechanisms for fluid and electrolyte absorption and secretion in the intestine? • The permeability of tight junctions between the epithelial cells determines ?

epithelial cells of the small intestine (~ 6.5L) and colon (~ 1.9L) excreted in feces. large quantities of electrolytes (Na+, Cl−, HCO3−, and K+) and water, but the epithelial cells lining the crypts of the small intestine also secrete fluid and electrolytes. This additional secretion contributes to the volume already in the intestinal lumen, which then must be absorbed. involve cellular and paracellular routes. whether fluid and electrolytes will move via the paracellular route or whether they will move via the cellular route. The tight junctions in the small intestine are "leaky" (have low resistance) and permit significant paracellular movement, whereas the tight junctions in the colon are "tight" (have a high resistance) and do not permit paracellular movement.

Diarrhea • Diarrhea is a major cause of death worldwide. Serious illness or death may be caused by the rapid loss of large volumes of extracellular-type fluid from the GI tract. The previous discussion emphasizes the enormous potential for fluid loss from the gastrointestinal tract, as much as 9 L or more per day. • In diarrhea, the loss of ? • In addition to circulatory collapse, other disturbances caused by diarrhea are related to the ? • The causes of diarrhea include ?

extracellular-type fluid results in decreased extracellular fluid volume, decreased intravascular volume, and decreased arterial pressure. The baroreceptor mechanisms and the renin-angiotensin II-aldosterone system will attempt to restore blood pressure (pressure natriuresis mechanism), but these attempts will be futile if the volume of fluid lost from the GI tract is too great or if the loss is too rapid. specific electrolytes lost from the body in the diarrheal fluid, particularly HCO3− and K+. Diarrheal fluid has a relatively high concentration of HCO3− because the fluids secreted into the GI tract have a high HCO3− content including salivary, pancreatic, and intestinal juices. Loss of HCO3− (relative to Cl−) causes hyperchloremic metabolic acidosis with normal anion gap. Diarrheal fluid also has a high concentration of K+ because of flow-rate-dependent K+ secretion by the colon. Excessive loss of K+ from the GI tract results in hypokalemia. decreased absorptive surface area, osmotic or secretory disturbances.

Digestion and absorption are the ultimate functions of the GI tract. o Digestion: the chemical breakdown of ingested foods into absorbable molecules. The digestive enzymes are secreted in ? o Absorption: the movement of nutrients, water, and electrolytes from the lumen of the intestine into the blood, and this can be achieved via two paths: ? In the cellular path, ? In the paracellular path, ?

salivary, gastric, and pancreatic juices and also are present on the apical membrane of intestinal epithelial cells. a cellular path and a paracellular path. the substance must cross the apical (luminal) membrane, enter the intestinal epithelial cell, and then be extruded from the cell across the basolateral membrane into blood. Absorptive processes are aided by transporters in the apical and basolateral membranes. substances move across the tight junctions between intestinal epithelial cells, through the lateral intercellular spaces, and into the blood.

b) Calcium 2+ • Ca is absorbed in the ? • Its most important action is to promote ? • In vitamin D deficiency or when there is failure to convert vitamin D to 1,25-dihydroxycholecalciferol (as occurs in chronic renal failure), there is inadequate ?

small intestine and depends on the presence of the active form of vitamin D, 1,25-dihydroxycholecalciferol. Ca2+ absorption from the small intestine by inducing the synthesis of vitamin D-dependent Ca2+- binding protein (calbindin D-28 K) in intestinal epithelial cells. Ca2+ absorption from the GI tract. In children, inadequate Ca2+ absorption causes rickets, and in adults, it causes osteomalacia.

Diarrhea : Decreased Surface Area for Absorption ? Osmotic Diarrhea ? Secretory Diarrhea?

• Disease processes that result in a decreased absorptive surface area including infection and inflammation of the small intestine cause decreased absorption of fluid by the GI tract. • Osmotic diarrhea is caused by the presence of non- absorbable solutes in the lumen of the intestine. For example, in lactase deficiency, lactose is not digested to glucose and galactose, the absorbable forms of this carbohydrate. Undigested lactose is not absorbed and remains in the lumen of the intestine, where it retains water and causes osmotic diarrhea (Fig. 46). Bacteria in the intestine may degrade lactose to more osmotically active solute particles, further compounding the problem. • Caused by excessive secretion of fluid by crypt cells (Fig. 46). The major cause of secretory diarrhea is overgrowth of enteropathic bacteria (pathogenic bacteria of the intestine) such as Vibrio cholerae or Escherichia coli. For example, the bacterial cholera toxin (Fig. 40) enters intestinal crypt cells by crossing the apical membrane (Step 1). Inside the cells, the A subunit of the toxin detaches and moves across the cell to the basolateral membrane. There, it catalyzes adenosine diphosphate (ADP) ribosylation of the αs subunit of the Gs protein that is coupled to adenylyl cyclase (Step 2). ADP-ribosylation of the αs subunit inhibits its GTPase activity, and as a result, GTP cannot be converted back to GDP. With GTP permanently bound to the αs subunit, adenylyl cyclase is permanently activated (Step 3), cAMP levels remain high, and the Cl− channels in the apical membrane are kept open (Step 4). The resulting Cl− secretion is accompanied by secretion of Na+ and H2O. The volume of fluid secreted into the intestinal lumen overwhelms the absorptive mechanisms of the small intestine and colon, leading to massive diarrhea.

Intestinal secretion Mechanism? • The Cl− channels of the apical membrane usually are closed, but ? Normally, the electrolytes and water secreted by intestinal crypt cells are?

• The epithelial cells lining the intestinal crypts secrete fluid and electrolytes. The basolateral membrane also has a Na+-K+-2Cl− cotransporter. This three-ion cotransporter brings Na+, Cl−, and K+ into the cells from the blood (Fig. 45). • Cl− moves into the cells on the Na+-K+-2Cl− cotransporter, and then diffuses into the lumen through Cl− channels in the apical membrane. Na+ ollows Cl− secretion passively, moving between the cells. • Finally, water is secreted into the lumen, following the secretion of NaCl. they may open in response to binding of various hormones and neurotransmitters (i.e. ACh, VIP) to receptors on the basolateral membrane. • The neurotransmitter or hormone binds to the basolateral receptor, activating adenylyl cyclase and generating cAMP in the crypt cells. cAMP opens the Cl− channels in the apical membrane, initiating Cl− secretion; Na+ and water follow Cl− into the lumen (Fig. 43). absorbed by intestinal villar cells. However, in diseases in which adenylyl cyclase is maximally stimulated (e.g., cholera), fluid secretion by the crypt cells overwhelms the absorptive capacity of the villar cells and causes severe, life-threatening diarrhea.

Ileum absorption?

• The ileum contains the same transport mechanisms as the jejunum plus a Cl−-HCO3− exchange mechanism in the apical membrane and a Cl− transporter, instead of an HCO3− transporter, in the basolateral membrane (Fig. 43 B). Thus, when H+ and HCO3− are generated inside the epithelial cells in the ileum, the H+ is secreted into the lumen via the Na+-H+ exchanger, and the HCO3− also is secreted into the lumen via the Cl−-HCO3− exchanger (rather than being absorbed into blood, as in the jejunum). The result of the combined Na+-H+ exchange and Cl−-HCO3− exchange in the apical membrane is net movement of NaCl into the cell, which then is absorbed. Thus, in the ileum, there is net absorption of NaCl, whereas in the jejunum there is net absorption of NaHCO3.