Enzymes pdf - د. هدف

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Digestive Secretion from Pancreas and Liver

Aim and objectives of lecture 3:

1.  to list and descibe the exocrine secretion of the pancrease
2.  to list and descibe the alkaline secretion of the pancrease
3.  to state the control of pancreatic exocrine secretion
4.  to list the functions of the liver
5.  to describe the secretion of bile
6.  to describe the role of bile acids in fat digestion and absorption
7.  to list the clinical significance of bile acid synthesis
8.  to state the pattern and control of bile secretion

The Pancreas

The pancreas, not the stomach, is the major organ that synthesizes and secretes the large

amounts of enzymes needed for digestion. Thus the pancreas plays a vital role in accomplishing

the followings:

• Acid must be quickly and efficiently neutralized to prevent damage to the duodenal mucosa

• Macromolecular nutrients - proteins, fats and starch - must be broken down much further before their

constituents can be absorbed through the mucosa into blood.

The pancreatic enzymes together with bile are poured into the lumen of the second

(descending) part of the duodenum, so that the bulk of the intraluminal digestion occurs distal

to this site in the small

intestine. However, pancreatic

enzymes cannot completely

digest all nutrients to forms

that can be absorbed. Even

after exhaustive contact with

pancreatic enzymes, a

substantial portion of

carbohydrates and amino

acids are present as dimers

and oligomers that depend for

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

final digestion on enzymes present on the luminal surface or within the chief epithelial cells

that line the lumen of the small intestine (enterocytes).

Exocrine Secretions of the Pancreas

Pancreatic juice is composed of two secretory products critical to proper digestion: digestive

enzymes and bicarbonate. The enzymes are synthesized and secreted from the exocrine acinar

cells, whereas bicarbonate is secreted from the epithelial cells lining small pancreatic ducts.

Pop quiz: The pancreas:

a) Functions as an exocrine gland as it secretes a number of digestive enzymes

b) Produces endocrine hormones associated with regulation of blood glucose levels

c) Releases bicarbonate ions to te lumen of the small intestine which act to neutralize chyme

d) All the above

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

1. Digestive Enzymes:

Proteases

Digestion of proteins is initiated by pepsin in the stomach, but the bulk of protein digestion is due

to the pancreatic proteases. Several proteases are synthesized in the pancreas and secreted

into the lumen of the small intestine. The two major pancreatic proteases are trypsin and

chymotrypsin both are endopeptidases, which are synthesized and packaged into secretory

vesicles as the inactive proenzymes trypsinogen and chymotrypsinogen.

•

Trypsin: Cleaves peptide bonds on the C-terminal side of arginines and lysines.

•

Chymotrypsin: Cuts on the C-terminal side of tyrosine, phenylalanine, and tryptophan

residues (the same bonds as pepsin, whose action ceases when the NaHCOs raises the pH

of the intestinal contents).

Once trypsinogen and chymotrypsinogen are released into the lumen of the small intestine, they

must be converted into their active forms in order to digest proteins, Trypsinogen is activated by

the enzyme enterokinase, which is embedded in the intestinal mucosa.

Once trypsin is formed, it activates chymotrypsinogen, as well as additional molecules of trypsinogen.

The net result is a rather explosive appearance of active protease once the pancreatic secretions

reach the small intestine.

Trypsin and chymotrypsin digest proteins into peptides and peptides into smaller peptides, but they

cannot digest proteins and peptides to single amino acids. Some of the other proteases from the

pancreas, for instance carboxypeptidase (exopeptidase) (This enzyme removes, one by one, the

amino acids at the C-terminal of peptides). But the final digestion of peptides into amino acids is largely the

effect of peptidases in small intestinal epithelial cells.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Pancreatic Lipase

The major form of dietary fat is triglyceride, or neutral lipid. A triglyceride molecule cannot be

directly absorbed across the intestinal mucosa. It must first be digested into a 2-monoglyceride

and two free fatty acids. The enzyme that performs this hydrolysis is pancreatic lipase.

Sufficient quantities of bile salts must also be present in the lumen of the intestine in order for

lipase to efficiently digest dietary triglyceride and for the resulting fatty acids and

monoglyceride to be absorbed. This means that normal digestion and absorption of dietary

fat is critically dependent on secretions from both the pancreas and liver.

Pancreatic lipase has recently been in the limelight as a target for management of obesity.

The drug orlistat (Xenical) is a pancreatic lipase inhibitor that interferes with digestion of

triglyceride and thereby reduces absorption of dietary fat. Clinical trials support the

contention that inhibiting lipase can lead to significant reductions in body weight in some

patients.

Amylase

The major dietary carbohydrate for many species is starch, a storage form of glucose in plants. Amylase

is the enzyme that hydrolyses starch to maltose (a glucose-glucose disaccharide), as well as the

trisaccharide maltotriose and small branchpoints fragments called dextrins.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Pop quiz: An alcoholic patient developed a pancreatitis that affected his exocrine

pancreatic function. He exhibited discomfort after eating a high-carbohydrate meal. The

patient most likely had a reduced ability to digest which of the following?

a. Starch

b. Lactose

c. Fiber

d. Sucrose

e. Maltose

Other Pancreatic Enzymes

In addition to the proteases, lipase and amylase, the pancreas produces a host of other digestive

enzymes, including nucleases, gelatinase and elastase.

• Nucleases. These hydrolyze ingested nucleic acids (RNA and DNA) into their component

nucleotides.

• Elastase: Cuts peptide bonds next to small, uncharged side chains such as those of alanine

and serine.

Pop quiz: the following list describes four major digestive enzymes. Which one of te

following is incorrect?

a. Salivary amylase-salivary glands-mouth

b. Pepsin-gastric glands- stomach

c. Nuclease-small intestine- stomach

d. Lipase-pancrease-small intestine

2. Bicarbonate and Water

Epithelial cells in pancreatic ducts are the source of the bicarbonate and water

secreted by the pancreas. The mechanism of bicarbonate secretion is essentially the

same as for acid secretion parietal cells and is dependent on the enzyme

carbonic anhydrase. In pancreatic duct cells, the bicarbonate is secreted into the

lumen of the duct and hence into pancreatic juice.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Control of Pancreatic Exocrine Secretion

Secretion from the exocrine pancreas is regulated by both neural and endocrine controls. During
interdigestive periods, very little secretion takes place, but as food enters the stomach and, a little later,
chyme flows into the small intestine, pancreatic secretion is strongly stimulated.
Pop quiz: Regarding pancreatic secretion:

a.  Pancreatic secretion is inhibited by gastrin secreted by G cells
b.  Pancreatic acinar cells contain trypsin
c.  Cholecystokinin inhibits secretion from the exocrine pancreas
d.  The introduction of acid into the duodenum stimulates pancreatic secretion

Cholecystokinin

: This hormone is synthesized and secreted by enteric endocrine cells located in the

duodenum. Its secretion is strongly stimulated by the presence of partially digested proteins and fats
in the small intestine. As chyme floods into the small intestine, cholecystokinin is released into
blood and binds to receptors on pancreatic acinar cells, ordering them to secrete large quantities
of digestive enzymes. It also stimulates the gallbladder to release bile and the pancreas to
produce pancreatic enzymes.

Secretin

: This hormone is secreted in response to acid in the duodenum. The predominant

effect of secretin on the pancreas is to stimulate duct cells to secrete water and bicarbonate.
As soon as this occurs, the enzymes secreted by the acinar cells are flushed out of the
pancreas, through the pancreatic duct into the duodenum. It also stimulates the liver to
secrete bile.

Gastrin

: This hormone, which is very similar to cholecystokinin, is secreted in large amounts by the

stomach in response to gastric distention and irritation, in addition to stimulating acid secretion
by the parietal cell; gastrin stimulates pancreatic acinar cells to secrete digestive enzymes.

Pop quiz:: The names of the hormones that influence pancreatic secretion and are also

important for secretion and flow of bile include:

a.  Cholecystokinin and secretin
b.  Cholecystokinin and gasretin
c.  Gastrin and secretin
d.  Insulin and secretin
e.  Glucagon and insulin

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

The Liver

The liver is the largest gland in the body and performs an astonishingly large

number of tasks that impact all body systems. One consequence of this complexity is

that hepatic disease has widespread effects on virtually all other organ systems.

The three fundamental roles of the liver are:

Vascular functions

: including formation of lymph and hepatic phagocytic system.

Metabolic achievements

in control of synthesis and utilization of

carbohydrates, lipids and proteins.

Secretory and excretory functions

, particularly with respect to the synthesis

of secretion of bile.

The latter is the only one of the three that directly affects digestion - the liver,

through its biliary tract, secretes bile acids into the small intestine where they

assume a critical role in the digestion and absorption of dietary lipids.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Secretion of Bile and the Role of Bile Acids in Digestion

Bile is a complex fluid containing water, electrolytes and a battery of organic

molecules including bile acids, cholesterol, phospholipids and bilirubin that flows

through the biliary tract into the small intestine. There are two fundamentally

important functions of bile in all species:

• Bile contains bile acids, which are critical for digestion and absorption

of fats and fat-soluble vitamins in the small intestine.

• Many waste products are eliminated from the body by secretion into bile

and elimination in feces.

Pop quiz: The components of bile include: bile salts, bile pigments, cholesterol and various
electrolytes. Which of the components in bile have digestive functions?

a.  bile salts
b.  Glucoronic acid
c.  bile pigments
d.  cholesterol
e.  all of the above

The secretion of bile can be considered to occur in two stages:

• Initially, hepatocytes secrete bile into canaliculi, from which it flows into bile

ducts. This hepatic bile contains large quantities of bile acids, cholesterol and

other organic molecules.

• As bile flows through the bile ducts it is modified by addition of a watery,

bicarbonate-rich secretion from ductal epithelial cells.

In humans: the gall bladder stores and concentrates bile during the fasting state.

Typically, bile is concentrated five-fold in the gall bladder by absorption of water and

small electrolytes - virtually all of the organic molecules are retained.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Secretion into bile is a major route for eliminating cholesterol. Free cholesterol is

virtually insoluble in aqueous solutions, but in bile, it is made soluble by bile acids

and lipids like lethicin. Gallstones (Cholelithiasis) most of which are composed

predominantly of cholesterol, result from processes that allow cholesterol to

precipitate from solution in bile.

Role of Bile Acids in Fat Digestion and Absorption

Bile salts are formed in the hepatocytes by a series of enzymatic steps that convert

cholesterol to cholic or chenodeoxycholic acids. The rate limiting step is

hydroxylation at the 7-alpha position. These reactions include the activity of 8

enzymes belonging to either monooxygenase or dehydrogenase enzyme

classes.

The most abundant bile acids (primary bile acids ) are:

1. chenodeoxycholic acid (45%) and

2. cholic acid (31%).

Within the intestines the primary bile acids are acted upon by bacteria and

converted to the secondary bile acids, identified as

1. deoxycholate (from cholate) and

2. lithocholate (from chenodeoxycholate).

Chenodiol is a natural bile acid that blocks production of cholesterol . Chenodiol

(Chenix), is used to dissolve gallstones in patients who cannot tolerate surgery.

This

action leads to gradual dissolution of cholesterol gallstones.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Synthesis of bile acids is one of the predominant mechanisms for the excretion of

excess cholesterol. However, the excretion of cholesterol in the form of bile acids is

insufficient to compensate for an excess dietary intake of cholesterol.

Bile acids are conjugated with glycine or taurine and secreted as Na

(or K

) salts.

Conjugation causes a decrease in their pKa values, making them more water-

soluble.

Bile acids are carried from the liver

through ducts to the gallbladder,

where they are stored for future use.

The ultimate fate of bile acids is

secretion into the intestine, where they aid in the emulsification of dietary lipids. In the

gut the glycine and taurine residues are removed and the bile acids are either excreted

(only a small percentage) or reabsorbed by the gut and returned to the liver. This

process of secretion from the liver to the gallbladder, to the intestines and finally

reabsorbtion is termed the enterohepatic circulation.

Enterohepatic Recirculation

After the bile acids has been released into the small intestine via the bile duct to play an

integral role in the absorption of dietary lipids and lipid soluble vitamins. More than

90% of the bile salts are actively reabsorbed (by a sodium-dependent co-

transport process) from the ileum into the hepatic-portal circulation from where they are

cleared and resecreted by the liver to once again be stored in the gall bladder. This

secretion/reabsorption cycle is called the Enterohepatic Circulation.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Pop quiz: regarding the bile:

a. Bile is diluted in the gall bladder

b. Bile salts are hydrophobic molecules

c. Most bile salts are absorbed in the terminal ileum

d. Bile salts are the breakdown products of hemoglobin

Systemic circulation: supplies nourishment to all of the tissue located throughout your

body, with the exception of the heart and lungs because they have their own systems.

Systemic circulation is a major part of the overall circulatory system.

Portal circulation: Blood from the gut and spleen flow to and through the liver before

returning to the right side of the heart. This is called the portal circulation and the large

vein through which blood is brought to the liver is called the portal vein.

The net effect of this enterohepatic recirculation is that each bile salt molecule is

reused about 20 times, often two or three times during a single digestive phase.

Note: liver disease can dramatically alter this pattern of recirculation - for instance, sick

hepatocytes have decreased ability to extract bile acids from portal blood and damage to the

canalicular system can result in escape of bile acids into the systemic circulation. Assay of

systemic levels of bile acids is used clinically as a sensitive indicator of hepatic disease.

Bile acids contain both hydrophobic (lipid soluble) and polar (hydrophilic)

faces. The amphipathic nature enables bile acids to carry out two important

functions:

1. Emulsification of lipid aggregates

: Bile acids have detergent action

on particles of dietary fat, which causes fat globules to break down

or be emulsified into minute, microscopic droplets. Emulsification is not

digestion per se, but is of importance because it greatly increases the

surface area of fat, making it available for digestion by lipases, which

cannot access the inside of lipid droplets.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

2. Solubilization and transport of lipids in an aqueous environment

: Bile

acids are lipid carriers and are able to solubilize many lipids by

forming micelles - aggregates of lipids such as fatty acids, cholesterol

and monoglycerides - that remain suspended in water. Bile acids are

also critical for transport and absorption of the fat-soluble vitamins.

Clinical Significance of Bile Acid Synthesis

Bile acids perform four physiologically significant functions:

1. Their synthesis and subsequent excretion in the feces represent the only

significant mechanism for the elimination of excess cholesterol.

2. Bile acids and phospholipids solubilize cholesterol in the bile, thereby

preventing the precipitation of cholesterol in the gallbladder.

3. They facilitate the digestion of dietary triacylglycerols by acting as

emulsifying agents that render fats accessible to pancreatic lipases.

4. They facilitate the intestinal absorption of fat-soluble vitamins.

Pattern and Control of Bile Secretion

The flow of bile is lowest during fasting, and a majority of that is diverted into the

gallbladder for concentration. When chyme from an ingested meal enters the

small intestine, acid and partially digested fats and proteins stimulate secretion

of cholecystokinin and secretin. These enteric hormones have important effects

on pancreatic exocrine secretion. They are both also important for secretion and

flow of bile:

Cholecystokinin:

The name of this hormone describes its effect on the

biliary system - cholecysto = gallbladder and kinin = movement. The

most potent stimulus for release of cholecystokinin is the presence of fat in

the duodenum. Once released, it stimulates contractions of the gallbladder

and common bile duct, resulting in delivery of bile into the gut.

Lecture 3

Thursday 26/9/2013

Dr Hedef D.El-Yassin

ِ◌ ِ◌

Prof.

2013

Secretin

: This hormone is secreted in response to acid in the duodenum.

Its effect on the biliary system is very similar to what was seen in the

pancreas - it simulates biliary duct cells to secrete bicarbonate and water,

which expands the volume of bile and increases its flow out into the intestine.

Conclusions:

1. Pancreatic juice contain enzymes capable of digesting all 4 major foodstuff

2. In pancreatic duct cells, the bicarbonate is secreted into the lumen of the duct and

hence into pancreatic juice

3. The introduction of acid into the duodenum stimulates pancreatic secretion together

with other hormonal secretagogues

4. Liver has a number of functions some of which are:

a. Vascular functions:

b. Metabolic achievements.

c. Secretory and excretory functions

5. The secretion of bile can be considered to occur in two stages:

a. Initially, hepatocytes secrete bile into canaliculi, from which it flows into bile

ducts. This hepatic bile contains large quantities of bile acids, cholesterol and

other organic molecules.

b. As bile flows through the bile ducts it is modified by addition of a watery,

bicarbonate-rich secretion from ductal epithelial cells.

6. Bile acids have a vital role in fat digestion and absorption as mentioned in the text

7. Bile acids perform four physiologically significant functions as mentioned in the text

8. Cholecystokinin and secretin have important effects on pancreatic exocrine secretion.

They are both also important for secretion and flow of bile: