Unit VI- Pancreatic and Biliary Secretion Flashcards
1
Q
Digestive Enzymes
A
Salivary- Amylase, Lingual lipase
Gastric- pepsin
Pancreatic- amylase, trypsin, chymotrypsin, carboxypeptidase, elastase, lipase-colpase, phospholipase A2, cholesterol esterase- nonspecfic lipase (1 L digestive juices/day)
Intestinal- enterokinase, disaccharidases (maltase, sucrase, lactase, trehalase, isomaltase), peptidases (aminooligopeptidase, dipeptidase)
2
Q
Proteases
A
- digest proteins
- Trypsinogen
- chymotrypsinogen
- procarboxypeptidase A and B
- zymogens have no enzymatic activity until activated in the gut
3
Q
Lipases
A
- digest fats
- lipase
- phospholipase
4
Q
Amylases
A
-digest carbohydrates
5
Q
Nucleases
A
- digest nucleic acid
- ribonuclease
- deoxyribonuclease
6
Q
Pancreatitis
A
-the pancreas becomes inflamed and the digestive enzymes are activated before they reach the intestine causing damage to the pancreas
7
Q
Pancreas
A
- most important digestive gland
- 1 L of fluid secreted per day
- Exocrine secretions(into ducts thence to the lumen) : aqueous juice high in HCO2- from centro-acinar and duct cells; enzyme juice from acinar cells and centro-acinar cells into the intercalary ducts which merge into the secretory ducts- then the secretion flow through the ducts of Wirsung and Santorini and are delivered into the duodenum
-endocrine secretions (into blood) from islets of langerhands regulate blood sugar and metabolism; glucagon secreted by alpha cells, insulin secreted by beta cells, somatostatin secreted by delta cells
8
Q
Pancreatic Aqueous Secretion
A
- bicarbonate neutralizes acid from stomach and allows pancreatic enzymes to function at their optimal neutral pH
- pepsin is inactivated at neutral pH, and thus cannot attack the duodenal mucosa
- neutralization of pH prevents damage to duodenal and intestinal mucosa by gastric acid
- aqueous secretion also serves to dilute the enzyme juice
- aqueous secretion originates in the centro-acinar cells and epithelial cells of intercalary ducts
9
Q
Organization of the Exocrine Pancreas
A
- fundamental secretory unit is composed of an acinus and an intercalated duct
- intercalacted ducts merge to form intralobular ducts which in turn merge to form interlobular ducts and then the main pancreatic duct
- the acinar cell is specialized for protein secretion
- large condensing vacuoles are gradually reduced in size and form mature zymogen
10
Q
Synthesis and Secretion of Enzymes
A
- originates in pancreatic acinar cells
- formed on ribosomes accumulate in rough surfaced cisternae
- smooth surfaced vesicles containing enzymes bud off, coalesce to form zymogen granules that usually contain pro-enzymes
- mature zymogen granules fuse with apical membrane and contents are discharged into lumen of acinus during secretion
11
Q
Pancreatic Acinar Cells Showing Potentiation of Enzyme secretion by secretin and CCK
A
- vagal stimulation is via ACh
- CCK, ACh, and gastrin increase intracellular calcium
- secretin and VIP increase cAMP via G coupled receptor which activates Gs, which adenylate cyclase which activates cAMP
- ACh- binds muscarinic receptor Gq coupled increase PLC make PIP2 and DAG
- secretin and CCK act synergistically- their effect when both are present is greater than the sum of their effects when either is acting alone
- VIP is a neurotransmitter in the gut normally not important in pancreatic secretion, but it becomes important in certain pancreatic tumors known as vipomas, which result in a watery diarrhea
- note that secretin and CCK potentiate each others actions both on pancreatic enzyme secretion
12
Q
VIP
A
- vasoactive intestinal peptide
- neurotransmitter in the gut normally not important in pancreatic secretion but it becomes important in certain pancreatic tumors which result in watery diarrhea
13
Q
Secretion of Chloride by the Acinar Cells
A
- the Na-K pump creates the inwardly directly Na+ gradient across the basolateral membrane
- the Na/K/Cl cotransporter produces the net Cl- uptake, driven by the Na+ gradient, which is generated by the Na-K pump
- rise in intracellular K+ that results from the activity of the pump and cotransporter is shunted by basolateral K_channels that provide an exit pathway for K+ (CCK and cholinergic neurotransmitter ACh stimulators of Cl- secretion-probably through phosphorylation of basolateral and apical ion channels)
- intracellular Cl- establishes the electrochemical gradient that drives Cl- secretion into the acinar lumen through apical membrane Cl- channels
- the movement of Cl- into the lumen makes the transepithelial voltage more lumen negative, driving Na into the lumen via tight junctions
14
Q
Na and HCO3- secretion by pancreatic duct cells
A
- diffusion of CO2 from the blood across the basolateral membrane into the duct cell
- hydrated by carbonic anhydrase to carbonic acid which dissociates to form H+ and HCO3-
- proton moves across basolateral membrane by Na+/H+ exchanger or an electrogenic proton pump
- bicarbonate accumulates in duct cell and exits across apical membrane via Cl-/HCO3- exchanger
- chloride channel is CFTR which is activated by secretin using cAMP, which stimulates PKA
- there is also a Ca2+ activated K channel
- CCK uses Ca2+ as second messenger to potentiate action of secretin
- K+ leaves the cell to to prime the Na+/K+ pump increasing the rate of secretion by the duct cell
- this generates negative transmembrane PD- driving force to move Na+ and K+ ions into the lumen via cation selective paracellular pathway
15
Q
Features of Aqueous Secretion
A
- venous blood is acidified during secretion by an electrogenic proton pump and by Na+/H+ exchange in the basolateral membrane; tends to negate “akaline tide”
- in the intestinal phase both secretin and cholecystokinin (CCK) stimulate aqueous secretion by pancreatic duct cells
16
Q
Secretin
A
-using cAMP as its second messenger, activates the CFTR Cl- channel thereby replenishing lumenal Cl- needed for Cl-/HCO3- exchange
17
Q
Cholecytokinin
A
- CCK
- acts via PLC to increase the intracellular concentration of Ca++ this potentiates the action of secretin by priming the Na+/K+ ATPase
- apical k+ channel is activated by Ca++
- increased K+ efflux primes the Na+/K+ -ATPase
18
Q
Composition of pancreatic juice and flow rate
A
- secreted fluid is high in HCO3- as seen at fast rates of secretion
- HCO3- exchanges with Cl- in ducts when rate of secretion is low
- Na+ and K+ concentration remain constant at different flow rates
- -the exchange hypothesis accounts for the increase in bicarbonate with increase secretory rate
19
Q
Cystic Fibrosis
A
- when CFTR channel is defective pancreatic secretions are thick and viscous, thus clogging the pancreatic ducts and interfering with digestion
- pulmonary mucous is also thick with viscous, causing dyspnea (labored breathing) and premature death
- aqueous secretion is needed to dilute the pancreatic enzyme secretion and reduce its viscosity
20
Q
Regulation of Pancreatic Secretion
A
- pancreatic secretion is in 3 stages. The first 2 are low in volume and high in enzyme content
- cephalic phase: vagal stimulation has greater effect on enzyme secretion from acini than on ductal aqueous secretion
- gastric phase:-distension of body of stomach induces pancreatic enzyme secretion by vago-vagal reflex
- antral distension release gastrin which stimulates acinar cells to secrete enzymes (and the oxyntic parietal cells to secrete HCl)
- intestinal phase: secretion and cholecystokinin (CCK) released into the blood from intestinal cells in response to products of digestion
21
Q
Secretin
A
- 27 amino acid peptide hormonne released into blood by S cells in duodenal mucosa in response to acid entering the intestine
- natures antacid because it inhibits gastric acid secretion and release of gastrin
- but stimulates gastric chief cells to secrete pepsinogen
- elicits aqueous secretion by pancreatic duct cells with secondary effect on acinar cells
- secretion is high in volume, high in HCO3 and low in enzyme content
22
Q
Cholecystokinin
A
- 33 amino acid peptide released into blood from I cells in duodenal mucosa in response to fatty acids or amino acids entering the duodenum
- elicits enzyme secretion by acinar cells and also potentiates aqueous secretion during intestinal phase
- also causes gallbladder contraction and relaxes sphincter of Oddi to release bile from gallbladder into duodenum
- also slows gastric emptying
- pancreatic enzyme secretion is high in enzyme content, low in volume
23
Q
Composition of Bile
A
- a yellow green alkaline solution containing bile salts, bile pigments, cholesterol, neutral fats, phospholipids and electrolytes
- bile salts are cholesterol derivatives that emulsify fat, facilitate fat and cholesterol absorption, help solubilize cholesterol
- enterohepatic circulation recycles bile salts
- the chief bile pigment is bilirubin, a waste product of heme
24
Q
Biosynthesis of Bile Salts
A
-the rate limiting step in bile acid formation is the addition of the hydroxyl group at position 7 by cholesterol 7 alpha-hydroxylase. Expression of this enzyme is reduced by bile acid and increased by cholesterol
25
Bile acids
- steroid hormones, made by liver and activating a nuclear hormone receptor to regulate expression of cholesterol 7 alpha-hydroylase
- production must be carefully balanced since at high levels they have carcinogenic properties
- liver conjugates primary and secondary bile acids with glycine or taurine to their respective bile salts
- the resulting bile salt is named for the bile acid and the conjugating amino acid
26
Choleretic
-an agent that stimulates the liver liver to increase output of bile
27
Bile acid sequestrants
-bind bile acids and prevent reabsorption from the gut and can be used to lower cholesterol
28
Bile salts
- amphipathic, they contain both a hydrophobic end (steroid nucleus) and a hydrophilic end. All contain the same hydrophobic end, but the hydrophilic ends differ
- they emulsify and solubilize fats and steroids (cholesterol)
- water solubility is conferred by the presence of -OH groups and ionized groups
- non conjugated bile salts have a pK of 7
- conjugated with glycine (75%) or taurine (25%) in the liver.
- glycine conjugates have pK of 3.7; taurine conjugated have a pK of 1.5
- therefore at pH 7 virtually all conjugated bile salts are anionic- they are very water soluble
29
Bile is secreted into Canaliculi
- bile is produced and secreted continuously by hepatocytes of the liver
- secreted into bile canaliculi which empty into bile ducts
30
Bilary Function
- Bile ducts -> hepatic ducts -> common bile duct -> duodenum
- cystic duct -> gall bladder
- when sphincter of Oddi is open bile is free to flow into the duodenum. When closed it is diverted into the galbladder
- stored and concentrated in gall bladder
- CCK contracts the gall bladder and relaxes the Sphincter of Oddi
- necessary for digestion and absorption of lipids as well as elimination of cholesterol and bile pigments
- composed of bile acids (-50%), phospholipids (25%), cholesterol (4%), bile pigment (2%) inorganic ions and IgA
31
Daily Bile Salt Turnover
- bile salts serve to emulsify fats and cholesterol in the intestine
- bile salt balance
- total bile salt pool: 3-4g
- daily secretion by liver: 12-25 g
- bile salts are reabsorbed and secreted twice during a meal and several times daily via the enterohepatic circulation
- daily loss in feces and replaced by synthesis in liver -0.5g
- hepatic production of bile acids is the major route of cholesterol and steroid hormone breakdown
- body makes 800 mg of cholesterol every day and 50% of that used to make bile salts
32
Bilary Secretion
- bile captured from the intestine flows to the liver through the portal vein
- then it is absorbed by the hepatocytes
- finally it is secreted into the canaliculus
- bile returns to the liver bound to albumin
- it is taken up by the liver by specific transporters: sodium taurocholate cotransporting polypeptide (CTCP) and organic anion transporting polypeptide (OATP)
33
Bile Acid Secretion
- bile acid-independent secretion of watery HCo3- rich fluid by cholangiocytes of the ducts and ductules similar to pancreatic aqueous secretion- stimulated by secretin
- bile acid-dependent secretion by hepatic parenchymal cells
- stimulated to secrete by bile acids returning to lover in portal blood
- synthesis of bile acids is inhibited by bile acids returning to liver via portal blood (feedback inhibition)
34
Enterohepatic Circulation of Bile Acids and Salts
- most bile acid are reabsorbed as conjuated bile salts in the terminal ileum through an Na+-coupled cotransporter (ASBT)
- bacteria deconjugate a small amount of bile salts to unconjugated bile acids which are passively absorbed by nonionic diffusion
- bacteria also dehydroxylate primary bile acids to secondary bile acids
- some are captured and returned to liver others are excreted in the feces
- bile salt malabsorption caused by terminal ileum resection can cause chronic diarrhea
- bile acid sequestrants is often an effective treatment
35
BA Concentration in gallbladder
- bile pigments, bile salts, cholesterol, lecithin and fatty acids are concentrated in the gallbladder
- results from active transport of Na+, Cl- and HCO3- out of lateral membranes of gallbladder epithelial cells and continued micellar formation
- isotonic fluid reabsorbed by the gallbladder epithelium
- the apical step is parallel Na-H exchange and Cl-HCO3 exchange
- because Na-H exchange is faster net secretion of acid into lumen occurs
- basolateral step of NaCL absorption is mediated by the NaK pump and Cl channels
- K channels provide a route for basolateral K+ recycling
- water follows passively through the tight junctions and through the basolateral membrane
36
Release of Bile from Gallbladder
- Neural-vagus
- Hormonal-CCK
- relaxes sphincter of Oddi and contracts the gallbladder
- the gallbladder like the stomach responds to cephalic stimuli, such as highly emotional situations
37
Approximate composition of human bile in liver and gallbladder
- isosmotic to plasma but the total number of ions exceeds 300 mOsmolar, due to formation of micells consisting of bile salts, lecithin and cholesterol
- Gallbladder bile are 10C
38
Bile Micelles
-serve as solvents for hydrophonic waste products to be removed from the body and hydrophobic components of the diet to be captured from the intestine
39
Formation of gallstones
1) supersaturation of cholesterol- in liver
2) nucleation and precipitation- seeding of cholesterol crysals or microstones- probably in gallbladder
3) growth of microstones to form macrostones
15% lecithin
80% bile salts
5% cholesterol
