Hepatobiliary Function

1. Hepatobiliary Function Lecture 28 Friday, March 9, 2007 Refs. Medical Physiology Chapter 45 and Ganong Chapter 26

2. Water absorption • Water moves either way across the mucosa. • Water follows electrolytes (osmotic gradient) • 98% of water that enters the gut is resorbed • Saline cathartics work because they are poorly absorbed salts and retain water in the lumen.

3. Water Recycling Gan T25-3

4. Chloride movement • Cl- enters the basolateral membrane of enterocytes via K+-Na+-2Cl- cotransporters. • Cl- is secreted into lumen through Cl- channels. • Some channels are activated by cAMP. • Disease caused by Vibrio cholerae illustrates importance of chloride channels: • In cholera, the bacterium (Vibrio cholerae) remains in the lumen but causes severe watery diarrhea by secreting cholera toxin. • Part of the cholera toxin enters the cell and causes increase in cAMP which activates the Cl- channel. • Oral rehydration with glucose helps because the sodium-dependent glucose cotransporter is independent of cAMP and Cl- channels.

5. Movement of ions across enterocytes in small intestine Gan 25-7

6. Absorption of vitamins • Most vitamins are absorbed in the upper small intestine • Vitamin B12 is absorbed in the ileum. • Intrinsic factor necessary for absorption is secreted by parietal cells in stomach. • Fat-soluble vitamins are A, D, E, and K. • If fat absorption is is deficient, ADEK will be low. • Water-soluble vitamins are B12, folate, thiamin, riboflavin, niacin, pyridoxine, pantothenate, biotin and ascorbic acid. • Except for B12 and folate, absorption is by Na+-dependent cotransporters.

7. Iron absorption • Iron is essential for formation of hemoglobin. • In normal individual, iron levels are tightly controlled. • Amount absorbed equals the amount lost. • Almost all absorption of iron occurs in the duodenum via DMT1. • Iron can be stored in cell attached to ferritin. • Iron is transported in the blood bound to transferrin.

8. Absorption of iron (in duodenum) Gan 25-8Ferric reductase is required to convert Fe3+ to Fe2+.FP is ferroportin 1 in the basolateral membrane.TF is transferrin, a plasma protein made by the liver.

9. Principal functions of the liver • Formation and secretion of bile • Nutrient and vitamin metabolism • Inactivation of substances • Endogenous- steroids and other hormones • Exogenous- drugs, toxins • Synthesis of plasma proteins • Immunity/phagocytosis

10. Components of bile • Bile acids- 50% of organic material • Majority of bile acids are conjugated, ionized and associated with Na+ as bile salts. • Phosphatidylcholine- 40% of organic material • Cholesterol- 4% of organic material • Bile pigments • Bilirubin is the major one; secreted as a glucuronide • Water • Electrolytes, inorganic salts, fatty acids, lecithin

11. Formation of bile • Hepatocytes • Primary bile acids are made in hepatocytes from cholesterol and excreted into bile. • Hepatocytes take up reabsorbed bile salts from sinusoids and excrete into canaliculus • Bile ducts • Bile duct cells (cholangiocytes) secrete electrolytes mainly NaHCO3 and modify bile. • Secretin increases the secretion of NaHCO3 by the ducts • Gallbladder • Reabsorbs fluid and acidifies bile.

12. Human bile acids. The numbers in the formula for cholic acid refer to the positions in the steroid ring. Ganong 26-22

13. Primary bile acids • Cholic acid • Chenodeoxycholic acid • Both are made by hepatocytes from cholesterol, periportal hepatocytes are specialized for oxidative processes

14. Secondary bile acids • Are made in the colon from the primary bile acids. • Colonic bacteria convert: • cholic acid to deoxycholic acid • chenodeoxycholic acid to lithocholic acid • Lithocholic acid is least soluble and is mostly excreted in stool. • Deoxycholate is absorbed from the colon.

15. Properties of bile acids • Aliphatic molecules • Acid has low water solubility. • Cholic acid with 3 OH groups is most soluble • Conjugation with glycine or taurine increases water solubility. • Conjugation makes them ionized at the pH of bile. • Usually associated with Na+ therefore salts.

16. Enterohepatic circulation of bile salts. The solid lines entering the portal system represent bile salts of hepatic origin, whereas the dashed lines represent bile salts resulting from bacterial action. Ganong 26-24

17. Uptake of bile acids • Hepatocytes use a number of transporters. • An important one is the NTCP: • Na-taurocholate cotransporting polypeptide • NTCP is a Na -coupled transporter • Has a high affinity for conjugated bile acids • Can transport unconjugated bile acids, other steroids and a variety of drugs • Unconjugated bile acids can enter by diffusion.

18. Physiologic functions of bile • Role in digestion of lipids: • Emulsify dietary lipids • Facilitate absorption by forming micelles • Without bile up to 50% of fat is excreted in stool. • Without bile there is severe malabsorption of fat-soluble vitamins • Role in excretion of wastes: • Cholesterol • Bile pigments • Other toxic chemicals

19. Bile salts increase lipid absorption Gan 25-4

20. Mixed micelle. Cross section of disk-shaped bile acid-lipid mixed micelle with free fatty acids and cholesterol in its hydrophobic interior. The surface of each bile acid that faces outward is hydrophilic because of the polar peptide bond and the carboxyl and OH groups. Ganong 26-23

21. Components of bile flow. MP 45-10

22. Bile production • Bile acid-dependent • Bile acid-independent • Bile made by pericentral (centrilobular hepatocytes) • Bile duct • Secretin

23. Bilirubin metabolism and excretion • Most of the bilirubin comes from the breakdown of hemoglobin (mainly from senescent RBCs) • In the tissues, especially Kupffer cells and spleen, • Heme is oxidized by heme oxydase to biliverdin. • Biliverdin is reduced by biliverdin reductase to bilirubin. • Water insoluble bilirubin is carried by albumin to the liver. • Hepatocytes conjugate bilirubin by adding glucuronic acid and excrete it into the bile. • Some bilirubin glucuronide enters plasma and is excreted by the kidney. • In the colon, bacteria convert bilirubin to urobilinogens; some of these are absorbed.

24. Metabolism of bilirubin in the liver. P, intracellular binding proteins; UDPGA, uridine diphosphoglucuronic acid; UDP, uridine diphosphate. Ganong 26-25

25. Glucose metabolism • Hepatocytes take up glucose by facilitated diffusion. • The transport protein is GLUT-2 • Hepatocyte uptake of glucose is not dependent on insulin. • Hepatocytes store glucose as glycogen. • Hepatocytes also synthesize glucose from amino acids (gluconeogenesis).

26. Urea formation • Deamination of amino acids occurs in the liver. • Products are keto acid and NH4+. • NH4+ and NH3 are in equilibrium. • Most of the NH4+ is converted to urea in the liver. • Urea is transported into the extracellular space by an aquaporin. • Urea enters the blood and is excreted by the kidney. • If hepatocytes cannot make urea, blood NH3 rises. • High levels of blood NH3 cause NH3 intoxication (encephalopathy).

27. Amino acid metabolism and urea formation in hepatocytes. MP 45-14