12 - Pancreatic and Bile Secretions

pancreatic secretion overview

pancreas produces about 1.5L/day of exocrine secretion

• composition → digestive enzymes (organic), electrolytes (inorganic)

• isotonic and alkaline → high HCO₃^- content

  • Na⁺ and K⁺ → about the same as plasma

  • Cl^- → much lower than plasma

  • HCO₃^- → much higher than plasma

acinar and ductal secretions

• acinar cells → primary secretion

  • digestive enzymes as inactive zymogens

  • isotonic NaCl-rich fluid

• ductal cells → secondary modification

  • convert NaCl to NaHCO₃-rich alkaline fluid

  • secrete HCO₃^- and water

  • absorbe Cl^-

pancreatic anatomy

• main pancreatic duct joins common bile duct → empties together through sphincter of Oddi

• CCK relaxes sphincter of Oddi → pancreatic juice and bile flow into duodenum

pancreatic acinar peptide secretions

• proteases → digest proteins, inactive zymogens

  • endopeptidases: trypsinogen, chymotrypsinogen, proelastase

  • ectopeptidases: procarboxypeptidase A, procarboxypeptidase B

• lipases → digest lipids

  • triacylglycerol hydrolase (pancreatic lipase)

  • prophospholipase A

  • cholesterol ester hydrolase

• amylase → ⍺-amylase

• nucleases → ribonuclease, deoxyribonuclease

• other peptides → not enzymes

  • pro-colipoase → cofactor for triacylglycerol hydrolase

  • trypsin inhibitor (PSTI/SPINK1) → prevents immature maturation of trypsin

  • monitor peptide → key CCK stimulus

zymogen activation

occurs only in duodenum, only pepsin activated in stomach by low pH

• trypsinogen converts to trypsin by duodenal enterokinase

  • pancreatic trypsin inhibitor prevents activation in pancreas

• trypsin activates every other protease zymogen from pancreas

acinar zymogen secretion

zymogens secretion from pancreatic acinar cells

• Ach, CCK, GRP → trigger intracellular Ca²⁺ release

• VIP, secretin → trigger cAMP release

• Ca²⁺ and cAMP prompt zymogen granules to move toward apical membrane for fusion and exocytosis

acinar electrolyte secretion

isotonic NaCl secretion from pancreatic acinar cells

• Cl^- channels on apical side allow Cl^- to exit into lumen

  • CCK and Ach stimulate Cl^- secretion

• negative charge in lumen pulls Na⁺ and water paracellularly

• basolateral Na⁺/K⁺ pumps and Na⁺/K⁺/Cl^- cotransporter maintain gradients

control of CCK

• release from I cells → stimulated by nutrients and pancreatic releasing peptides (CCK-RP, monitor peptide)

• stimulatory pathways:

  • endocrine → bind acinar cells to increase enzyme secretion

  • vago-vagal reflex → stimulate pancreatic secretions

    • vagal afferents → ENS → Ach, VIP → secretion

• trypsin degradation of CCK-RP and monitor peptide inhibited by protein → keep CCK release at optimal level

  • increased trypsin → inhibit I cell from releasing CCK

  • increased protein → inhibit trypsin, stimulate CCK release

ductal electrolyte secretion

isotonic NaHCO₃ secretion from pancreatic ductal cells, with Cl^-/HCO₃^- exchanger on luminal membrane as key player

• secretin → binds receptor on ductal cell, potentiated by CKK and Ach

• Cl^-/HCO₃^- exchanger → HCO₃^- secreted into lumen, Cl^- moves into cell

• CTFR → Cl^- recycled into lumen for continued exchange

• Na⁺ and water → pulled into lumen paracellularly for isotonic NaHCO₃

control of secretin

• release from S cells → stimulated by acid (pH < 4.5) in duodenum

• stimulates ductular bicarbonate secretion

• inhibits parietal cells → decrease acid secretion

• restores neutral pH for pancreatic enzymes

synergistic vs additive effects

• CCK + Ach → additive effect

  • both use same Ca²⁺ pathway

• secretin + CCK/Ach → synergistic effect

  • secretin uses cAMP

  • CCK/Ach use Ca²⁺ pathway

contribution of pancreatic secretions

• cephalic phase → 20%; neural pathway

  • vagal stimulation → Ach release

• gastric phase → 5%; neural and endocrine pathways

  • stomach distention, peptides

  • vago-vagal → Ach and GRP release

  • gastrin → CCK-A receptors in pancreas

• intestinal phase → 75%; neural, endocrine, paracrine pathways

  • secretin → acid release

  • lipid, peptides

  • enteropancreatic vago-vagal reflexes

bile

produced in the liver

• modified in bile ducts

• stored/concentrated in gallbladder

• released into duodenum when needed for lipid digestion

canalicular bile secretion

made by hepatocytes and released into bile canaliculi and intrahepatic bile ducts

• bile acid-independent flow → contains phospholipids (lecithin), cholesterol, bile pigments, detoxified agents

• bile acid-dependent flow → bile salts, isotonic electrolyte solution

  • volume increases when more bile acids are secreted

  • due to enterohepatic circulation

ductular bile secretion

bile flowing through duct is modified by cholangiocytes, producing isotonic NaHCO₃

• apical side

  • Cl^-/HCO₃^- exchanger → secretes HCO₃^-

  • Cl^- channels → supply Cl^- for exchange

  • aquaporin-1 → water movement to lumen

• stimulated by secretin → increases cAMP, and activates Cl^- channel and Cl^-/HCO₃^- exchanger

canalicular secretion of bile acid and nomenclature

• primary → synthesized in liver

  • cholic acid (CA, trihydroxyl)

  • chenodeoxycholic acid (CDCA, dihydroxy)

• secondary → converted to secondary bile acid by colon bacteria

  • deoxycholic acid (DCA)

  • lithocholic acid (LCA)

  • ursodeoxycholic acid (UDCA)

• conjugation of bile acids → remaining in intestinal lumen

  • bile salts

bile flow and anatomy

hepatic ducts → common hepatic duct → joins cystic duct → common bile duct → sphincter of Oddi → duodenum

• sphincter of Oddi closed → bile flows into gallbladder and becomes concentrated while remaining isotonic

• during meals → CCK release causes gallbladder contraction and sphincter relaxation, allowing bile to flow into duodenum

bile salts

liver conjugates bile acids with glycine or taurine to become bile salts, or conjugated bile acids

• prevent passive absorption in proximal small intestine

• stay in lumen long enough to assist lipid digestion

• amphipathic nature → allows formation of micelles

  • solubilize FFAs, monoglycerides, cholesterol, phospholipids, fat-soluble vitamins

  • carry lipolytic products to brush border for absorption

mechanism of bile salts

• pancreatic lipases digest triglycerides to become lipolytic products

• bile salts surround these lipids and form micelles

• micelles deliver lipids to enterocyte surface for absorption

bile release as function of CCK

CCK is triggered by fat, proteins, and peptides in duodenum

• contracts gallbladder

• relaxes sphincter of Oddi via vago-vagal reflex with VIP and NO

• stimulates pancreatic enzyme secretion

enterohepatic circulation

bile acids must be reused multiple times per meal — 2-4g total acid pool, but 10-40g/day bile acid secretion

• liver secretes bile salts to gallbladder and duodenum

• bile salts form micelles for lipid absorption

• after lipids absorbed, only bile salts remain in lumen

• terminal ileum contain ABST (apical sodium-dependent bile acid transporter) that actively reabsorbs bile salts

• bile salts return to liver and reconjugated to be resecreted into bile