Eight Flashcards

1
Q

Describe pancreatic acinar secretions as well as what happens to the secretions in the ducts.

A

Pancreatic secretions (like most salivary secretions for that matter) are produced

in a structure termed an acinar gland. The acinus itself looks like a cul-de-sac type street

with acinar cells at the end of the cul-de-sac and tubular (or ductal) cells that run down

the street. Initially pancreatic fluid is produced as an enzyme rich concoction by the

acinar cells with electrolyte concentrations resembling plasma, but what is finally

secreted into the duodenum has been heavily modified by the ducts and contains not only

enzymes but also large amount of bicarbonate and is relatively depleted in chloride ions.

This is illustrated below:

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2
Q

What are the secreted pancreatic proteases? Which is most abundant? What happens when they’re released? Describe their activation and function. Describe the complete digestion and absorption of proteins in the intestine.

A

The pancreatic proteases include trypsin, chymotrypsin, as well as carboxypolypeptidases. By far, the most abundant of these proteolytic enzymes is trypsin. The pancreatic enzymes are stored and released in inactive forms and (in health) are converted to active forms only once secreted into the intestinal lumen. The inactive form of trypsin is trypsinogen (that ‘ogen’ thing comes up time and again starting with pepsinogen in the stomach which in the presence of gastric acid converts to pepsin). Trypsinogen is metabolized into its active form in the duodenum by a brush-border enzyme called enterokinase or by trypsin molecules that had already been activated in the duodenum.

Trypsin is also responsible for the activation of the other pancreatic proteases. The pancreatic proteases are produced and released in enormous excess when compared with physiologic digestive needs. In other words, even if 90 to 95 percent of inherent pancreatic function is compromised, the amount of pancreatic protease produced should be adequate to meet digestive needs. The activation of pancreatic proteases is shown here:

Specific proteases break peptides at defined amino acid combinations. This allows the digestion of different proteins with a relatively limited number of enzymes.
Intraluminal protein digestion is largely mediated by pancreatic endopeptidases. These proteases cleave specific internal peptide bonds yielding peptides that are the preferred substrates for carboxypeptidases (exopeptidases), which cleave the carboxyterminal amino acids. The products are free amino acids and oligopeptides. As they say a picture is worth one thousand words:

The next step is the absorption of protein digestion products. The oligopeptides generated by pancreatic protease digestion are hydrolyzed further into tripeptides,
dipeptides, and free amino acids by a series of brush border enteropeptidases. At least six different active transport systems (some shown on the top of the next page) are responsible for absorbing amino acids and oligopeptides. The absorbed tripeptides and dipeptides are hydrolyzed into amino acids by cytosolic peptidases. Amino acids are transported across the basolateral membrane mainly by passive mechanisms and are
cleared into the portal circulation.

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3
Q

What is the pancreatic digestive enzyme for carbs? What does it digest? What are its products? What bonds is it able to attack? What is the eventual fate of its products?

A

The pancreatic digestive enzyme for carbohydrates is pancreatic amylase which is released in its active form. Amylase hydrolyzes starches, glycogen, and other sugary
things (except cellulose) to form disaccharides and a few trisaccharides. Amylase is only able to attack the interior -1,4 bonds of polysaccharides. Polysaccharides are composed of chains held together by -1,4 bonds (digested by amylase) as well as -1,6 bonds (these bonds are not affected by amylase). The products of amylase digestion need to be further metabolized into monosaccharides by brush border enzymes in the small intestine before being absorbed.

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4
Q

Describe the two types of digestible starches in our diet? How do they differ? How are they hydrolyzed? What are their products? How does glycogen compare?

A

The typical diet contains about 300 grams of carbohydrates of which about half is starch and most of the rest is more simple sugars like sucrose, lactose, maltose, and fructose. There are two types of digestible starch in our diets; they are amylose and amylopectin. Amylose is made up of -1,4 linked linear chains of about 600 glucose residues. Amylopectin is a branched starch of about 6000 glucose residues again linked mostly by -1,4 bonds but these are punctuated (about every 20 glucose residues) by -1,6 branch points.

In the gastrointestinal lumen starch is hydrolyzed by salivary and pancreatic amylases. These -amylases are able to bind 5 glucose residues at the end of a chain and
cleave between the second and third -1,4 linked glucose residues. For amylase, which is linear, the end products are maltose (a disaccharide) and maltotriose (a trisaccharide). Remember, amylase is not able to cleave the -1,6 linkages that are present in amylopectin; these linkages also stearically hinder the cleavage of some of the -1,4 linkages. Therefore, the end product of amylase digestion of amylopectin include maltose, maltotriose, and branched -limit dextrins which contain an average of 5 to 10 glucose residues and one or more -1,6 bond. To see this illustrated, please refer to the top diagrams on the next page.

A third high-molecular weight oligosaccharide (though usually not characterized as a starch) is glycogen. Glycogen is similar to amylopectin except for more frequent -1,6 linkages. Glycogen is found in animal tissues where it serves as a short-term reservoir for glucose. The digestion of starches is shown on the
top of the next page with two illustrations showing the same idea to try and illustrate this. Go ahead, look at the pictures and reread the section—it’s probably worthwhile.

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5
Q

Describe what happens to carbs after amylase at the brush border? What enzyme splits most alpha 1,6 linkages? What other enzymes are involved? What channels are involved?

A

The oligosaccharide products of intraluminal starch digestion and ingested simple sugars are then delivered to the small bowel enterocytes. Brush border enzymes
(glucoamylase, sucrase, isomaltase, trehalase, and lactase) further hydrolyze these sugars to monosaccharides. The specific role that these brush border enzymes play is diagrammed as follows. Note that most -1,6 linkages are split by isomaltase.

Fructose is absorbed by passive diffusion. Glucose and galactose are absorbed into the cell via an active sodium/glucose (or galactose) cotransporter. Again, this is
shown in a diagram below. The glucose then enters the body through the Glut-2 channel.

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6
Q

What is the main pancreatice enzyme for fat digestion? What is another one? How are they activated? Why is the second enzyme necessary? What are their products? What inactivates the main enzyme?

A

The main pancreatic enzyme for fat digestion is pancreatic lipase. Pancreatic lipase is secreted in its active form. Bile salts from bile secretion (also drain into the intestine through the ampulla of Vater) will inhibit the action of lipase. A second molecule to aid in fat digestion is secreted by the pancreas. This second molecule—
called procolipase is secreted in a 1:1 ratio with lipase. Trypsin digests procolipase (you’d think they would call it colipaseogen, but NO…that would be too easy) to its
active form, colipase. Colipase allows lipase to work even in the presence of bile salts. Pancreatic lipase-colipase complexes hydrolyze triglycerides into two fatty acid
molecules and one monoglyceride. An important feature of lipase is that it is rapidly and irreversibly inactivated by exposure to an acid environment (pH

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7
Q

Describe the emulsification of fat that occurs in the small bowel. What role does secretin play? What emulsifying agents are involved and what is their role?

A

There is one major problem with the absorption of fat and cholesterol. These compounds are not water-soluble. Therefore, digestion and absorption are impossible without a mechanism to deal with this. The first step in the process of solubilizing and digesting fats is emulsification. Emulsification is simply the conversion of large fat droplets into innumerable smaller droplets; this increases the surface area of lipids to aid in enzymatic hydrolysis. Emulsification is partly mechanical—churning of fat in the stomach. In the setting of a large amount of fat in the intestine, a hormone (secretin) is released which not only stimulates the release of pancreatic lipase but also slows gastric emptying to allow more time for mechanical emulsification. Emulsification is partly chemical and involves bile acids, lecithin, and phospholipids (all three of these emulsifying agents are present in bile). Emulsifying agents decrease the surface tension at the oil-water interface.

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8
Q

Describe the function of lipase in fat digestion? Describe the function of other pancreatic enzymes in fat digestion.

A

After emulsification, digestion can begin. Digestion is largely the result of pancreatic lipase/colipase complexes (I’ll just call it pancreatic lipase from now on). Pancreatic lipase cleaves the 1 and 3 ester linkages of triglycerides; it does not affect the 2 ester linkage of triglycerides. The result of this is that triglycerides are broken down to
two fatty acid chains (from the 1 and 3 position of the glycerol) and one 2-monoglyceride (a fatty acid that remains adherent to the 2 position of the glycerol molecule). This is shown below:

Other pancreatic enzymes including phospholipase A2 and cholesterol esterase (a.k.a. nonspecific esterase) are capable of hydrolyzing dietary phospholipids, cholesterol ester, and esters of fat soluble vitamins. Additionally, cholesterol esterase is able to cleave all three ester linkages of triglycerides—see why it is called the nonspecific esterase?

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9
Q

Describe the importance of micelles. What are their components? What do they house? Where do they end up? How are fats absorbed into enterocytes? What happens after that?

A

Bile salts do more that just help to emulsify fats for hydrolysis. Bile salts also play a role in aiding absorption of lipolytic products. Bile salts are amphipathic which
means they have both hydrophobic and hydrophilic portions. If enough bile salts are in the intestine the critical micellar concentration is achieved. At the critical micellar concentration, bile salt monomers form molecular aggregates called micelles. These micelles have a hydrophobic core in which fatty acids are soluble and carried. Theoutside however is not hydrophobic and this facilitates transport into the cell. After the fat is absorbed, the bile salts are mostly reabsorbed and used again (enterohepatic circulation). The general principles are below and on the next page:

For review, the second diagram on the preceding page shows triglyceride digestion and solubilization in the duodenum. Ingested triglyceride becomes fat droplets
after emulsification in the stomach and duodenum. The triglyceride is then hydrolyzed by pancreatic lipase to release fatty acids and monoglycerides. Incorporation of these digestion products into micelles increases their solubility by many orders of magnitude. In addition to fat, cholesterol and fat-soluble vitamins (A, D, E, and K) are dependent upon micellar solubilization for absorption.

The second diagram shows the mucosal absorption of lipids. The fatty acids and monoglycerides are released from the micelles and are absorbed by passive and carrier mediated mechanisms. To be completely honest, and who would want to be any other way, the exact mechanism of the transport of fat into enterocytes is not fully understood. In the enterocytes, the lipids are re-esterified into triglycerides and bind with lipoproteins
to form chylomicrons (loosely translates to small fatty globs). Chylomicrons are then secreted by exocytosis into the lymphatics.

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10
Q

Describe pancreatic bicarb secretion and its cellular mechanism.

A

When stimulated, the pancreas can deliver fluid that contains a concentration of bicarbonate that is over 5 times greater than in plasma. This provides the alkali necessary to neutralize the hydrochloric acid emptied into the duodenum from the stomach. The mechanism for the bicarbonate production is shown and reviewed below.

To produce bicarbonate, pancreatic cells use carbon dioxide in their cytoplasm (from diffusion to the interior of the cell from the blood or from intracellular metabolism)
and water to produce carbonic acid (H2CO3); this reaction is aided by the enzyme carbonic anhydrase. The carbonic acid dissociates into bicarbonate and hydrogen ions as shown above. The bicarbonate is then actively transported (along with a Na+ electrical neutrality—not shown above) into the pancreatic duct via a chloride-
bicarbonate exchanger. The chloride is then released back into the lumen via a passive channel. This chloride channel is the CFTR or cystic fibrosis transmembrane regulator. As the name would suggest, this is the defective protein in the disease cystic fibrosis. The hydrogen ions formed by the dissociation of carbonic acid inside the cell are transported through the blood border into the tissue (and blood) in an exchange for sodium ions.

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11
Q

Describe the different phases of pancreatic secretion. Describe the regulation of pancreatic secretions including the hormones involved, their function, and what mediates their release.

A

The secretion of pancreatic fluids is stimulated by acetylcholine (from the vagus nerve) and secretin (secreted by proximal small bowel mucosa in response to food).

The baseline secretion of pancreatic fluids is minimal. With just the thought of feeding pancreatic stimulation begins—this vagus nerve mediated pancreatic function is
referred to as the cephalic phase. Animal experiments suggest that the cephalic phase will induce 20 percent of the pancreatic secretion which is seen during a meal and that it tends to produce an enzyme rich pancreatic fluid with a less robust aqueous secretion.

During the gastric phase of pancreatic secretion, distension of the stomach probably further contributes to vagal stimulation of pancreatic secretion. The hormone gastrin is thought to play little role in human pancreatic secretion.

The presence of fat, protein, and acid in the duodenum accounts for the majority of the stimulation of pancreatic function in what is termed the intestinal phase. Two
closely related hormones are responsible for intestinal phase pancreatic stimulation; they are secretin and cholecystokinin.

Secretin is a hormone produced by S-cells in the intestine. These S-cells are mucosal cells which sense the luminal pH and produce secretin in response to a pH below 4.5. S-cells will release progressively more secretin in a linear fashion as the pH drops to about 3 when the S-cells are maximally stimulated. Secretin serves to increase intestinal pH both by inducing pancreatic bicarbonate secretion (both from the liver and the pancreas) and by decreasing acid production by gastric parietal cells.

Cholecystokinin (a.k.a. CCK) is a hormone with probably both endocrine (released into blood stream) and paracrine (released into local tissues where it tickles vagal afferents while making the sound “goochie goochie”). The major function of CCK is to stimulate pancreatic enzyme production. By the way, I made the “goochie goochie” part up myself so it is best to ignore that for the boards. CCK is produced by I-cells in the proximal intestine. I-cells release CCK in response to short peptides, amino acids, and fatty acids (longer then eight carbon atoms). Additionally, there is believed to be a luminal peptide secreted by some duodenal cells termed CCK-releasing peptide (CCK-rp). The peptide is broken down by active pancreatic proteases and therefore this may serve in part as a feedback mechanism to slow pancreatic enzyme release when sufficient enzyme is already present.

One final note, there is considerable overlap. So vagal stimulation, secretin, and CCK have some defined function in terms of bicarbonate or enzyme production they do overlap regarding influence over the pancreas.

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