Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Cell Bio 6- Exocrine Pancreas and Hepatobiliary Function of the
Document related concepts
Transcript
Cell Bio 6- Exocrine Pancreas and Hepatobiliary • • Function of the Exocrine Pancreas Secrete pancreatic enzymes • Carbohydrates--Amylase • Protein • Trypsin (most abundant) and chymotrypsin • Proteins → polypeptides • Procarboxypeptidase • Polypeptides → amino acids • Fat--Lipase Neutralize acids-- Enzymes require neutral pH Functional Anatomy • Pancreatic ducts • Wirsung (major) • Enters duodenum with the common bile duct • Sphincter of Oddi • Santorini (minor) • Enters duodenum proximal to Wirsung • Sphincter of Oddi • Regulates flow • Bile • Pancreatic juice • Prevent reflux into the pancreatic ducts • Acini • Acinar cells • Extensive rough endoplasmic reticulum (RER) & Golgi • Apical zymogen granules • Enzyme producing cells • Centroacinar cells • Little RER • Modify electrolyte content • Ducts • Duct cells • HCO3- secretion • Modify electrolyte content • Intercalated ducts • Intralobular ducts • Interlobular ducts Cell Bio 6- Exocrine Pancreas and Hepatobiliary Exocrine Pancreas Enzymes Secreted as zymogens • Proenzymes • Proenzymes • Trypsinogen • Chymotrypsinogen • Procarboxypeptidase • Proelastase • Prolipase Why proenzymes? • Function • Prevents digestion of the acinar cells and pancreatic ducts • Regulation of Pancreatic Enzymes • Enteropeptidase (enterokinase) activates • Typsinogen → trypsin (trypsin is key player) • Secreted by the small intestinal mucosa upon contact with chyme • Trypsin activates • More trypsinogen • Chymotrypsinogen → chymotrypsin • Procarboxypeptidase → carboxypeptidase • Proelastase → elastase • Prolipase → lipase • Trypsin inhibitor • Secreted by pancreatic acinar cells when trypsinogen is secreted • Prevents the activation of trypsinogen within the acinar cells and the pancreatic ducts • Clinical note: Sphincter of Oddi dysfunction can lead to pancreatitis because activated trypsin is refluxed into the pancreatic duct. Electrolyte Secretions • HCO3- and H2O-- Neutralize HClLike plasma • Isotonic • Na+ and K+ concentration-- Remain constant at all flow rates • HCO3- primary anion • ↑ 5 fold when stimulated; Inverse concentration with Cl- Cell Bio 6- Exocrine Pancreas and Hepatobiliary HCO3- Secretion • Duct cells • Electrolyte modification • Opening of CFTR Cl-channels • Activated by ↑in cytosolic cAMP • ↑luminal Cl- drive Cl-/HCO3- antiporters and HCO3-secretion • CFTR dependent (cystic fibrosis) • Pancreatic dysfunction in cystic fibrosis • HCO3- generation • Na+/HCO3- symporter (NBC-1) • Catalyzed intracellularly by carbonic anhydrase Regulation of Pancreatic Secretion • Phases • Cephalic • Enzyme secretion • Gastric • Vagovagal reflex • Intestinal • Most important • Mostly hormonal • Effector cells • Ductal cells • Acinar cells • Principal stimuli • Acetylcholine (ACh) enzyme secretion • Cholecystokinin (CCK) enzyme secretion • Secretin HCO3 secretion Cell Bio 6- Exocrine Pancreas and Hepatobiliary Regulation of Ductal Secretions • Duct cell stimulus • Secretin • Source • S cells : Small intestine mucosa • Effect Stimulate HCO3- release • Mechanism • Increases intracellular cAMP • Secretin stimulus • Duodenal pH<4.5 • Stimulates secretin release → Secretin secretes HCO3- from duct cells • Note: Vasoactive intestinal peptide (VIP) is structurally related to secretin. It also stimulates HCO3- release but is much weaker.. Regulation of Acinar Secretions • Acinar cell stimuli • ACh • CCK (primary) • Source • ACh –vagus nerve • CCK- I cells • Effect • Increase enzyme release • Mechanism • Increase intracellular Ca2+ • Source stimulus • ACh • Parasympathetic input • Vagovagal reflex • CCK • Long-chain fatty acids • Free amino acids Role of CCK on Acinar Secretions Note: Gastrin is structurally related to CCK. • Effect on acinar cells It also stimulates enzyme release but is • Direct effect on CCK1 receptors (previous slide) much weaker.. • Vagovagal reflex activation from the small intestine • Stimulates acinar cells through vagal neurotransmitter release • ACh, GRP and VIP (see previous slide) • Additional stimulants of CCK release • CCK-releasing peptide • Paracrine cells senses fatty acids and amino acids and release CCK-releasing factor which has a paracrine effect on I cells • Monitor peptide • Released by acinar cells into the gastric juice • Both CCK-RP and Monitor peptide • May be stimulated by neuronal input • Help match CCK release and subsequent pancreatic enzyme release to the meal • Feedback loop (degradation of the peptides once the ingested meal has passed) Cell Bio 6- Exocrine Pancreas and Hepatobiliary Cystic Fibrosis • • Mutation of the CFTR Cl- channel • Effects <0.05% of Caucasian infants • Abnormally thick secretions • Typically thought of as a lung disease. However… Digestive disorder • Meconium ileus 5-10% newborns with CF • 85-90% of patients with CF • Thickened pancreatic secretions decrease (block) the pancreatic duct • Diminished digestive ability • Malabsorption disorder • Pancreatitis Hepatobiliary System • Function • Produce bile • Aids in the digestion and absorption of lipids • Excretion • Bilirubin • Cholesterol • Storage of bile • Gallbladder • Reabsorption of bile Functional Anatomy • Liver • Hepatocytes • Produces Bile • Gallbladder • Stores Bile • Ducts • Right and left hepatic ducts • Common hepatic duct • Carries bile to the gallbladder and duodenum • Via cystic and common bile duct respectively • Common bile duct • Joins forces with the Evil pancreatic duct to become the Ampulla of Vater • Sphincter • Sphincter of Oddi • Regulates flow • Bile • Pancreatic juice • Bile canaliculi • Dilated intercellular space between hepatocytes • Drain into the bile duct • Drain into the gallbladder • Gallbladder storage • Between meals the sphincter of Oddi is closed so the bile is stored in the gallbladder • H2O absorbed. Bile is concentrated up to 5X original concentration • Released into the duodenum with eating Cell Bio 6- Exocrine Pancreas and Hepatobiliary Bile Produced by Hepatocytes Contents • Bile salt (Conjugated bile acid) • Bile pigment (Bilirubin) • Lipids: Cholesterol, Phospholipids • Proteins • Function • Digest lipids • Emulsifying fat • Micelles • Aggregates of fat droplets • Mixed lipids and bile salts • Increase surface area • Increase lipase action • Excrete • Bilirubin • Cholesterol Bile Acids • Produced • Hepatocytes • Cytochrome P450 oxidation of cholesterol • Primary bile acids • Cholic acid • Chenodeoxycholic acid • Secondary bile acids • Conversion of the primary bile acids by bacteria in the gut • Deoxycholic acid • Lithocholic acid • Conjugated in the liver • • Bile Salts • are bile acids conjugated with glycine or taurine, • and at duodenal pH are ionized BA-, • and form a complex with Na+. • Increases their water solubility • Limits their absorption • Bile salts are not absorbed until all the lipid is absorbed • Conjugated bile acids require active carrier-mediated transport for absorption • Function • Promote the intestinal absorption of lipids • Acts like a detergent • Excrete • Cholesterol Bile Storage • Stored and concentrated • Gallbladder • Hepatic bile vs. gallbladder bile • Gallbladder bile is highly concentrated • Significant H2O absorption Cell Bio 6- Exocrine Pancreas and Hepatobiliary Bile Lipids • Primary lipids in bile • Cholesterol • Cholesterol gallstones • Phospholipids • Phosphatidylcholine (lecithin) Bile Flow Canalicular bile flow • Bile acid-dependent secretion • Energy dependent • Na+/K+-ATPase • Bile salts • Taken up by the hepatocytes • New bile salts synthesized from cholesterol • Cholesterol and phospholipid secretion is coupled to bile salt secretion • Bile acid-independent secretion • Energy dependent • Secretion of HCO3• Note: Bilirubin is secreted into the canaliculus by a separate active transport process. Ductular secretion • Secretions • H2O • HCO3• Effected by CFTR mutations • Thickening of the bile secretions can result in obstruction Bile Acid Regulation • Highly regulated • Prevent toxicity to GI lining • Synthesis and secretion is regulated by the amount of bile acids in the hepatic portal circulation • Negative-feedback system • Between meals (low concentrations of bile acids in the portal blood) • High synthesis • Low bile acid-dependent flow • After a meal (high concentrations of bile acids in the portal blood) • Inhibits bile acid synthesis • Stimulates bile acid-dependent flow • Similar to Pancreatic Regulation • Cephalic phase • Gastric phase • Intestinal phase • Cephalic and gastric phases are the same as pancreatic secretions • Increased parasympathetic outflow from central and vagovagal inputs • Gallbladder constriction • Relaxation of the sphincter of Oddi • Intestinal phase • Primarily regulated by GI hormones Cell Bio 6- Exocrine Pancreas and Hepatobiliary • • • • Cholecystokinin (CCK) • Stimulus for release • Amino acids or free fatty acids in duodenum • Effect (endocrine) • Gallbladder contraction • Increases bile duct pressure • Relaxes the sphincter of Oddi • Stimulates the vagovagal reflex • Relaxes the sphincter of Oddi Secretin • Just like the pancreas • Stimulus for release • Acidic chyme • Effect • HCO3- secretion from duct cells Gastrin • Stimulates bile acid secretion • Direct effect on liver • Indirect • ↑acid → ↑secretin Steroids (estrogen and androgen) • Inhibit bile secretion • Clinical note: Reduced bile secretion is a side effect associated with HRT and contraception. Enterohepatic Circulation • Recycling of bile salts • Small intestine and liver • All bile acids = total bile acid pool = 2-4 grams • Important for the efficient use of bile salt and proper lipid absorption • Absorbed bile salts • Return to the hepatocytes via the portal vein • Attached to • Albumin • High-density lipoproteins (HDL) good guys. • Very efficient • 80% uptake Absorption of Bile Salts 1. Passive diffusion-- Entire small intestine • Small amount 2. Active carrier-mediated-- Apical Na+-dependent bile acid transporter (symporter) • Most important • Very efficient (Leaves < 5%) • Bile acid excretion is a way to eliminate cholesterol 3. Passive diffusion following deconjugation by bacteria • Form bile acids-- More lipophilic 4. Passive diffusion following dehydroxylation by bacteria • Form secondary bile acids • Deoxycholic acid - absorbed • Lithocholic acid - poorly absorbed Cell Bio 6- Exocrine Pancreas and Hepatobiliary Disease • Cholelithiasis (Gallstone) • Imbalance in the bile (most) • Too much cholesterol • Too little bile salts • Can form anywhere in the biliary tree • Consequences • Jaundice • Can cause pancreatitis • Colic • Severe visceral pain • Vomiting • Acute cholecystitis • More prevalent in women • Cholestasis • Blockade of bile flow (in liver) • Disruption of bile flow through the canaliculi • Symptoms • Bilirubin retention • Jaundice • Cholesterol retention • Deposition of cholesterol • Bile salt retention • Pruritus
