Unit 6 - Pancreatic and Biliary Secretions Flashcards
what are zymogens secreted by pancreas? what are they activated by?
trypsinogen (activated by enteropeptidase)
chymotrypsinogen (activated by trypsin)
procarboxypeptidase A and B
what causes inflammation in pancreatitis?
digestive enzymes are activated before they reach the intestine
what kind of enzymes does the pancreas secrete?
proteases
lipases
amylases
nucleases (ribonuclease and deoxyribonuclease)
what are the exocrine VS endocrine secretions of the pancreas? what do they do?
exocrine: into ducts to lumen
- aqueous juice: has bicarbonate made by duct and centro-acinar cells
- enzyme juice: secreted by acinar cells into intercalary ducts that merge into secretory ducts
- -secretions flow thru ducts of Wirsung and Sontorini to duodenum
endocrine secretions: into blood from islets of Langerhans regulate blood sugar and metabolism
- glucacon: from alpha cells
- insulin: from beta cells
- somatostatin: from delta cells
what are the actions of pancreatic aqueous secretion
bicarbonate neutralizes acid from stomach, and allows pancreatic enzymes to function at their optimal neutral pH
- pepsin is inactivated at neutral pH, so cannot attack duodenal mucosa
- neutralization of pH prevents damage to duodenal and intestinal mucosa by gastric acid
- aqueous secretion also serves to dilute enzyme juice
how is the exocrine pancreas organized?
-structure and function of acinar and duct cells
fundamental secretory unit is acinus + intercalated duct
- IDs merge to form intralobular ducts, which merge to form interlocular ducts, then the main pancreatic duct
- acinar cell is specialized for PRO secretion
- -large condensing vacuoles are gradually reduced in size, and form mature zymogen granules that store digestive enzymes in apical region
- duct cell is cuboidal cell with abundant mitochondria and secretes bicarbonate
- -small microvilli project from its apical membrane
what is the order of synthesis and secretion of enzymes in a cell? how does this relate to pancreatitis?
ribosomes on RER –> Golgi –> condensing vacuoles –> zymogen granules –> fuse with apical membrane so contents are discharged
-in pancreatitis, enzymes are released into the cell instead of being packaged in granules
how is VIP related to pancreatic secretion
vasoactive intestinal peptide (nt in gut) is not usually important in pancreatic secretion, but it’s important in pancreatic tumors (vipomas) that cause watery diarrhea
what do CCK, ACh, gastrin, secretin, and VIP do?
CCK, ACh, and gastrin –> Gq –> PLC –> DAG for PKC, and IP3 to increase intracellular Ca++
secretin and VIP –> Gs –> AC –> cAMP –> PKA
will alter phosphorylation of these regulatory PRO to cause vesicle insertion and PRO secretion
how do secretin and CCK act together?
synergistically
how does secretion of Cl- by acinar cells occur? what does this do to Na+?
Na/K pump causes inward Na+ gradient across basolateral membrane
- Na/K/Cl cotransporter (all going inside cell) produces net Cl- uptake driven by Na+ gradient
- increase intracellular [K+] is shuted by basolateraly [K+] channels
- intracellular [Cl-] establishes electrochemical gradient that drives Cl- secretion into acinar lumen thru apical membrane Cl- channels
- movement of Cl- into lumen makes transepithelial voltage more lumen-negative, driving Na+ into lumen via tight junctions
what stimulates NaCl secretion and how?
ACh and CCK stimulate it via phosphorylation of basolateral and apical ion channels
what is the membrane potential of pancreatic duct cells at rest and during secretion?
- 1 mV at rest
- 5 mV during secretion
what makes up 25% and 75% of pancreatic secretions?
25% is NaCl from acinar cells
75% is HaHCO3 from duct cells
how does secretion of isotonic NaHCO3 happen in pancreatic duct cells?
Cl-HCO3 exchanger puts Cl- into cell and HCO3 into lumen
- some HCO3- that enters lumen directly enters cell via Na/HCO3 cotransporter on basolateral membrane
- additional intracellular HCO3- is made by carbonic anhydrase via CO2 + OH-
- -OH- comes from splitting of H2O driven by extrusion of H+ into interstitial space by pump and Na/H exchanger
- lumen-negative voltage pulls Na+ into lumen via tight junction
what is the most powerful stimulus for HCO3- secretion from pancreatic duct cells? what else affects this? what are their mechanisms?
secretin
-activates AC, increases cAMP, stimulates PKA, and phosphorylates CFTR to activate it and replenish luminal Cl- for Cl-/HCO3- exchange
ACh and CCK also stimulate HCO3- secretion by activating Gq, to stimulate PLC, to release DAG (to stimulate PKC) and IP3, which releases Ca++ from internal stores
- apical K+ channel is activated by Ca++
- increased K+ effluz primes Na/K-ATPase
what does the rate of the apical Cl-/HCO3- exchanger depend on?
availability of substrate, including luminal Cl, which depends on the opening of the CFTR apical Cl- channel (cystic fibrosis transmembrane regulator)
-CFTR is activated by secretin
what are features of the aqueous secretion of pancreas?
venous blood is acidified during secretion by electrogenic H+ pump and Na/H exchange in basolateral membrane
- this negates the alkaline tide
- in intestinal phase, both secretin and CCK stimulate aqueous secretion by pancreatic duct cells
relationship between composition of pancreatic juice and pancreatic flow rate
electrolyte composition of aqueous secretion is function of rate of secretion
- when pancreatic flow rate changes, the [Na] and [K] concentrations in pancreatic juice remain constant, but [HCO3-] and [Cl-] change in reciprocal manner (maintained by Cl-/HCO3- exchanger in apical membrane of ductal cells)
- if rate is fast, will be high in HCO3-
- if rate is slow, will resemble plasma and extracellular fluid (higher in Cl-)
what does the “exchange hypothesis” mean?
HCO3- exchanges with Cl- in ducts when rate of secretion is low
-accounts for increase in bicarbonate with increased secretory rate
how does cystic fibrosis occur?
when CFTR channel is defective, pancreatic secretions are thick and viscous (enzymes), clogging pancreatic ducts and interfering with digestion, because aqueous secretion isn’t made
-pulmonary mucous is also thick and viscous, causing dyspnea and premature death
how is pancreatic secretion in the 3 stages:
- cephalic
- gastric
- intestinal
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
- distension of body induces pancreatic enzyme secretion by vaso-vagal reflex
- antral distension releases gastrin, which shares CCK receptor to stimulate acinar cells to secrete enzymes, and oxyntic parietal cells to secrete HCl - secretin and CCK released from intestinal cells in response to products of digestion
secretin
- structure
- what releases it and why
- what it does
27 AA peptide hormone released into blood by S cells in duodenal mucosa in response to acid entering intestine
- “nature’s antacid” b/c inhibits gastric acid secretion and gastrin release
- instead stimulates gastric chief cells to secrete pepsinogen, and causes aqueous secretion by pancreatic duct cells, with secondary effect on acinar cells
what is the volume, HCO3- concentration, and enzyme content of pancreatic aqueous secretion VS pancreatic enzyme secretion?
AS: high in volume and [HCO3-], low in enzyme content
ES: high in enzyme content, low in volume
CCK
- structure
- what releases it and why
- what it does
33 AA peptide released into blood by I cells in duodenal mucosa in response to FA or AA entering duodenum
- causes enzyme secretion by acinar cells, and potentiates aqueous secretion during intestinal phase
- causes GB contraction and relaxes sphincter of Oddi to release bile from GB into duodenum
- slows gastric emptying
what is butter an effective releaser of?
CCK
composition of bile
yellow-green, alkaline solution with bile salts/acids (50%), bile pigments (2%), cholesterol (4%), neutral fats, phospholipids (25%), IgA, and electrolytes
what are bile salts? what do they do?
cholesterol derivatives that:
- emulsify fat
- facilitate fat and cholesterol absorption
- help solubilize cholesterol
what does enterohepatic circulation do?
recycle bile salts
what is the chief pigment of bile?
bilirubin (waste product of heme)
what is the rate limiting step in bile acid formation? when is expression of this enzyme reduced and increased?
addition of hydroxyl group at position 7 by cholesterol 7 alpha-hydroxylase
-expression reduced by bile acid, and increased by cholesterol
progression of biosynthesis of bile salts
cholesterol + 7 alpha-hydroxylase –> primary bile acids + 7 alpha-dehydroxylase –> secondary bile acids + conjugation –> bile salts
-this all happens in the liver, such that glycine or taurine are conjugated to respective bile salts
what is a choleretic? what is an example
agent that stimulates liver to increase output of bile
-bile acid sequestrants can bind bile acids, prevent reabsorption from the gut, and lower cholesterol
how are bile salts named?
named for the bile acid and conjugating AA
what percentage of bile salts are primary and secondary? what percentage are conjugated with glycine or taurine?
70% primary, 30% secondary
75% glycine, 25% taurine
why can bile salts emulsify and solubilize fats and steroids?
they are amphipathic
-all contain the same hydrophobic end (steroid nucleus), but hydrophilic ends (-OH and ionized groups) differ
what does intestinal bacteria do to cholic and chenodeoxycholic bile salts? what percentage of bile salts are these?
cholic (3 OH; 35%) –> deoxycholic (2 OH; 25%)
chenodeoxycholic (2 OH; 35%) –> lithocholic (OH; 5%)
what is the pKa of
- non-conjugated bile salts
- glycine conjugates
- taurine conjugates
and what does this mean?
NCBS: 7 (at pH of 7, only half are ionized and effective amphipaths)
gly: 3.7 (almost all bile salts anionic, so very water soluble)
tau: 1.5 (almost all bile salts anionic, so very water soluble)
what is the active secretion VS passive permeation into canaliculi?
AS: bile salts, phosphatidylcholine, conjugated bilirubin, xenobiotics
PP: water, glucose, Ca, glutathione, AA, urea
passage from bile duct to duodenum or GB
bile ducts –> right/left hepatic ducts –> common hepatic duct –> common bile duct –> duodenum
-if sphincter of Oddi is closed, bile travels back up common bile duct to cystic duct –> GB
what does CCK do to the gall bladder and Oddi?
contracts GB and relaxes SoO
-necessary for digestion/absorption of lipids and elimination of cholesterol and bile pigments
what is the daily bile salt turnover?
total pool: 3-4 grams
daily secretion by liver: 12-25 grams
-bile salts are reabsorbed and secreted twice during a meal, and several times daily via enterohepatic circulation
daily loss in feces (replaced by liver): 0.5 grams
how much cholesterol is made by the body and how much of that is used to make bile salts?
800 mg cholesterol is made a day, and 50% of that is used to make bile salts
how is bile returned to the liver?
captured from intestines by albumin, and flows to liver thru portal vein
- absorbed by hepatocytes using NTCP and OATP (Na taurocholate and organic anion cotransporting polypeptides)
- secreted into canaliculis
what is bile acid-independent and -dependent secretion?
independent: watery HCO3-rich fluid by cholangiocytes of ducts and ductules (like pancreatic aqueous secretion)
- stimulated by secretin
dependent: by hepatic parenchymal cells
- stimulated to secrete by bile acids returning to liver in portal blood, but this causes negative feedback on bile acid synthesis
what does terminal ileum resection cause and how can it be treated?
causes bile salt malabsorption, which causes chronic diarrhea
-bile acid sequestrants are often effective treatment
where are most bile acids reabsorbed?
in terminal ileum as conjugated bile salts through Na-coupled cotransporter (ASBT)
-bacteria deconjugate some to unconjugated bile salts, which are passively absorbed by nonionic diffusion, or hydroxylate primary bile acids to secondary bile acids
how are bile constituents concentrated in the GB?
- active transport of Na+, Cl-, and HCO3- out of the luminal (HCO3-, H+) and interstitial membranes (K+, Na+, Cl-, H2O) of GB epithelial cells
- continued micellar formation
how does isotonic fluid reabsorption by GB epithelium occur?
- apical/lumenal parallel Na/H exchange and Cl/HCO3 exchange (NaCl enters cell)
- faster Na/H exchange causes net secretion of acid into lumen - basolateral Na/K pump and Cl- channels (NaCl exits cell to interstitum)
- K+ channels allow basolateral K+ recycling
- water passively follows via tight junctions thru basolateral membrane
what causes GB bile release?
neural (vagus), hormones (CCK), and cephalic stimuli (highly emotional situations)
-relaxes sphincter of Oddi and contracts GB
how do the following concentrations differ in liver and GB bile?
- Cl-
- HCO3-
- bile salts
- bilirubin
- cholesterol
- lecithin
- FAs
Cl: GB is 10x lower
HCO3: GB is 3x lower
bile salts, bilirubin: GB is 10x higher
cholesterol: GB is 6x higher
lecithin, FA: GB is somex higher
why is bile isosmotic to plasma in both liver and GB, even though the total number of ions exceeds 300 mOsms?
formation of micelles, consisting of bile salts, lecithin, and cholesterol
-each particle contributes equally to osmotic force, whether molecule, ion, or micelle
what do micelles do?
solvents for hydrophobic waste products to be removed from the body and hydrophobic components of diet to be captured from intestine
-above critical micelle concentration (CMC), bile salts are spontaneously self-associated into mixed micelles
what are the stages of gallstone formation?
- supersaturation of cholesterol - occurs in liver
- nucleation and precipitation - seeding of cholesterol crystals or microstones (probably in GB, uncertain mechanism)
- growth of microstones to macrostones
what are the most common type of stones in the US?
cholesterol gallstones
-pigment stones more common in far East and Africa
components of gallstones
15% lecithin
80% bile salts
5% cholesterol
what is cholecystitis?
inflammation of GB caused by blockage of cystic duct by gallstone
-causes backup of bile in GB, potentially damaging the organ
