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Physiology of Digestion and Absorption 2

Physiology of Digestion and Absorption 2. Professor John Peters e -mail: j.a.peters@dundee.ac.uk. Learning Objectives. After this lecture students, should be able to: Name the main molecular constituents of foodstuffs which can be digested in humans and those which cannot be digested

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Physiology of Digestion and Absorption 2

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  1. Physiology of Digestion and Absorption 2 Professor John Peters e-mail: j.a.peters@dundee.ac.uk

  2. Learning Objectives • After this lecture students, should be able to: • Name the main molecular constituents of foodstuffs which can be digested in humans and those which cannot be digested • State how the small intestine is well adapted for absorption • Explain how carbohydrate is digested to the monosaccharides, glucose, galactose and fructose • Appreciate how monosaccharides are transported into and out of enterocytes • Provide an account of protein digestion noting the role of endo- and exo-peptidases • Explain in outline how amino acids, dipeptides and tripeptides are transported into and out of enterocytes • State the problems posed by the digestion of fats and how these are overcome with bile salts etc. • State the events in the formation of small fat droplets and micelles • Describe how free fatty acids and monoglycerides are absorbed in the small intestine • Indicate how the absorption of free fatty acids and monoglycerides differs from that of cholesterol • Explain how chylomicrons are formed, transported and processed • Explain how the absorption of Ca2+ and iron are regulated processes • Outline the mechanisms that underlie the absorption of water- and fat- soluble vitamins • Explain why the absorption of vitamin B12 is a special case that requires a complex series of events

  3. Main Constituents of Food • Carbohydrates– approx. 400 g per day - • Starch (amylose and amylopectin – greater than 50% total carbohydrate ingested) • Cellulose (indigestible in humans - roughage) • Glycogen • Disaccharides (sucrose, lactose) • Lipids – approx. 25-160 g per day - • Triacylglycerols(approximately 90% of total lipid ingested as fats and oils) • Phospholipids • Cholesterol & cholesterol esters • Free fatty acids • Lipid vitamins • Proteins – approx. 70-100 g per day ingested, plus 35-200 g from endogenous sources • e.g. digestive enzymes and dead cells from GI tract

  4. The Small Intestine is Well Adapted for Absorption • Compared to a simple cylinder of identical dimensions surface area is increased by: • Circular folds • Villi • Microvilli (the brush border) 3-fold 30-fold 600-fold

  5. Carbohydrate Digestion (1) • Mouth • Commences with salivary -amylase • Stomach • Continues with salivary -amylase • Small intestine (duodenum) • Pancreatic amylase (enzyme secreted and free in lumen) • Oligosaccharidases (associated with the brush border membrane of enterocytes). Includes isomaltase and -glucosidase • Disaccharidases (associated with the brush border membrane of enterocytes). Includes sucrase, lactase and maltase

  6. Carbohydrate Digestion (2) Starch, glycogen Amylase - attacks internal -1,4 glycosidic linkages (not -1,4 as in cellulose) Maltose Maltotriose Isomaltose Isomaltase (Cleaves -1,6 bond) Maltase (Cleaves -1,4 bond) Glucose Glucose Enterocyte Enterocyte

  7. Carbohydrate Digestion (3) Sucrose Lactose Fructose Galactose Sucrase (Cleaves -1,2 bond) Lactase (Cleaves -1,4 bond) Glucose Glucose Enterocyte Enterocyte Nb. Deficiency in lactase causes the common condition lactose intolerance.

  8. Absorption of the Final Products of Carbohydrate Digestion: Glucose, Galactose and Fructose • Glucose and galactose are absorbed by secondary active transport; fructose by facilitated diffusion (occurs in duodenum and jejunum) Na+/K+ATPase Glucose (or galactose) 1 Glucose (or galactose) SGLT1 GLUT2 2 Na+ 2K+ GLUT5 3 Na+ Fructose Fructose H2O

  9. Digestion of Proteins • Stomach • HCl begins to denature proteins • Pepsin cleaves proteins into peptides • Duodenum • Pancreatic enzymes (trypsin, chymotrypsin) split peptide bonds between different amino acids • Brush border enzymes (aminopeptidase, carboxypeptidase, or dipeptidase) cleave amino acid at ends of molecule, or hydrolyse dipeptide • Final products • Amino acids • Dipeptides • Tripeptides • Oligopeptides • (Some intact proteins – very few)

  10. Protein Absorption Amino acids • Passive diffusion • Hydrophobic amino acids (e.g. tryptophan) • (Mostly by) active transport – against concentration gradient and also by facilitated transport in small intestine via: • Brush border – at least 7 different mechanisms • 5 are Na+-dependent co-transporters (secondary active transport) • 2 are Na+ independent • Basolateral border – at least 3 different mechanisms • Na+ independent (facilitated transport) Di- and tri-peptides • via H+-dependent mechanism at brush border (co-transport) • Further hydrolysed to amino acids within the enterocyte • Na+-independent systems at the basolateral border (facilitated transport)

  11. Simplified Scheme for Amino Acid and Peptide Absorption Lumen Amino acid Na+ Na+ H+ Peptide Na+/K+ATPase H+ H+ Peptide Secondary active transport Hydrolysis Facilitated transport Amino acid Na+ Na+ K+ Amino acid Amino acid K+ Interstitium

  12. Digestion of Lipids • Mouth • Lingual lipase (little effect) • Stomach • Gastric lipase (modest effect) • Small intestine • Emulsification by bile • Pancreatic lipase splits into fatty acids and monoglyceride Ingested Lipids • Fats / Oils – triacylglycerols (TAG) – 90 % of total • Phospholipids • Cholesterol and cholesterol esters • Fatty acids All are insoluble in water causing problems for digestion and absorption – only triacylglycerols are considered here.

  13. Lipid digestion of TAG by lipases O O O O O 1 H2CO C (CH2)16 CH3 • In Stomach • Heat and movements in stomach mix food with gastric lipase which begins digestion and forms an emulsion Triglyceride 2 HCO C (CH2)16 CH3 3 • Hydrolysis initially slow due to largely separate aqueous/lipid interface • As hydrolysis proceeds, rate increases due to fatty acids produced acting as surfactantsbreaking down lipid globules aiding emulsification • Emulsified fats ejected from stomach to duodenum Gastric lipase + H2O H2CO C (CH2)16 CH3 H2CO C (CH2)16 CH3 Diglyceride HCO C (CH2)16 CH3 CH3 (CH2)16 COOH + CH2OH Free Fatty acid (stimulates CCK release from duodenum and secretion of pancreatic lipase) • In duodenum • Pancreatic lipase - main lipid digestive enzyme • Aided by bile salts from gall bladder • HCO3- in pancreatic juice neutralises stomach acid - provides suitable pH for optimal enzyme action

  14. Role of Bile Salts (1) • Bile salts are amphipathic - • Bile salts secreted in bile from the gall bladder in response to CCK act as detergents to emulsify large lipid droplets to small droplets Hydrophilic (projects from surface of droplet - Hydrophobic (adsorbs onto droplet) Increased surface area for action of lipase _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Bile salts Large fat droplet • Failure to secrete bile salts results in: • Lipid malabsorption- steatorrhoea (fat in faeces) • Secondary vitamin deficiency due to failure to absorb lipid vitamins

  15. Role of Bile Salts (2) • Bile salts increase surface area for attack by pancreatic lipase, but block access of the enzyme to the lipid with the hydrophobic core of the small droplets • Problem solved by colipase, an amphipathic polypeptide secreted with lipase by the pancreas – binds to bile salts and lipase allowing access by the latter to tri- and di-glycerides Lipase Colipase Triglyceride Bile salt Small droplet

  16. Digestion by Pancreatic Lipase Produces 2-Monoglyceride and Free Fatty Acids O O O O 1 H2CO C (CH2)16 CH3 2 HCO C (CH2)16 CH3 Triglyceride 3 H2CO C (CH2)16 CH3 Pancreatic lipase + 2H2O CH3 (CH2)16 COOH CH3 (CH2)16 COOH CH2OH Free fatty acid + HCO C (CH2)16 CH3 CH2OH Free fatty acid 2-monoglyceride

  17. The Final Products of Lipid Digestion are Stored in, and Released From, Mixed Micelles Fatty acid Monoglyceride Bile salt Cholesterol Hydrophobic core Phospholipid

  18. Lipid Absorption (1) Free Fatty acids and monoglycerides • Transfer between mixed micelles and the apical membrane of enterocytes entering by the cell by passive diffusion Fatty acids Monoglycerides • Short chain (i.e. 6 carbon) and medium (i.e. 8-12 carbon ) fatty acids diffuse through the enterocyte, exit through the basolateral membrane and enter the villus capillaries • Long chain fatty (i.e.  12 carbon) fatty acids and monoglycerides are resynthesized to triglycerides in the endoplasmic reticulum and are subsequently incorporated into chylomicrons

  19. Lipid Absorption (2) – Chylomicron Formation Carried in lymph vessels to systemic circulation (subclavian vein) via the thoracic duct Monoglyceride Triglyceride synthesis Cholesterol esters Free fatty acid Nascent chylomicron Chylomicron Endoplasmic reticulum Phospholipid synthesis Apolipoprotein (ApoB-48) Exocytosis Central lacteal

  20. Lipid Absorption (3) – Chylomicron Processing • Chylomicron enters systemic circulation into the subclavian vein via the thoracic duct and distributed to tissues • Chylomicron triglyceride metabolised in capillaries (particularly muscle and adipose tissue) by lipoprotein lipase present on endothelial cells • Free fatty acids and glycerol released initially bind to albumen and are subsequently taken up by tissues • Remainder of chylomicron is a chylomicron remnant, enriched in phospholipids and cholesterol • Chylomicron remnant undergoes endocytosis by hepatocytes – cholesterol released to: • be stored • secreted unaltered in bile • oxidised to bile salts

  21. Lipid Absorption (4) – Cholesterol Absorption • Once thought to be passive (similar to free fatty acids and monoglycerides) • Now appreciated to be mainly due to transport by endocytosis in clatherin coated pits by Niemann-Pick C1-like 1 (NPC1L1) protein • Ezetimibe binds to NPC1L1, prevents internalization, and thus cholesterol absorption. Used in conjunction with statins in hypercholesterolaemia

  22. Absorption of Ca2+ • Occurs by passive (i.e.paracellular; whole length of small intestine) and active (i.e.transcellular; mainly duodenum and upper jejunum) transport mechanisms Ca2+ (high lumenal Ca2+) Ca2+ Ca2+-calbindin-D Ca2+ (low lumenal Ca2+) • With [Ca2+] in chyme 5 mM absorption is mainly active 3Na+ Ca2+ • Active Ca2+ absorption is regulated by 1,25-dihydroxyvitamin D3 (calcitriol) and parathyroid hormone (increases 1,25-dihydroxyvitamin D3 synthesis) Ca2+ (high lumenal Ca2+) Ca2+ channel (TRPV6) – expression increased by 1,25- dihydroxyvitamin D3 Ca2+-ATPase (PMCA1) – expression increased by 1,25-dihydroxyvitamin D3 Sodium/calcium exchanger (NXC1)

  23. Absorption of Iron • Iron – important constituent of haemoglobin, myoglobin, many enzymes Ferratin (storage form of iron) • 12-15 mg ingested daily – only 3-10 % absorbed (female more than male) Fe3+Fe2+ Apoferratin + Fe2+  Fe3+ (Vit C) Fe2+ Fe2+ + Transferrin e.g. haemoglobin synthesis Haem oxidase Transferrin-Fe2+ Haem Divalent metal transporter 1 (DMT1) Haem carrier protein 1 Ferroportin(negatively regulated by the hormone hepcidin released from liver when body iron levels are high) – major control on iron absorption

  24. Absorption of Vitamin B12 (cobalamin) • Present in minute amounts in the diet (5-15 g day – daily requirement approximately 6 g per day, hence efficient and selective absorption required Vitamin B12 ingested in food Salivary glands secrete haptocorin Stomach acid releases vitamin B12 from food Haptocorin binds vitamin B12 released in stomach Stomach parietal cells release intrinsic factor Pancreatic proteases digest haptocorin in small intestine, vitamin B12 released Vitamin B12 binds to intrinsic factor in small intestine Vitamin B12-intrinsic factor complex absorbed in terminal ileum by endocytosis

  25. Absorption of Vitamins Fat soluble vitamins (i.e. A, D, E and K) • Incorporated into mixed micelles • Usually passively transported into enterocytes • Incorporated into chylomicrons, or VLDLs • Distributed by intestinal lymphatics Water soluble vitamins (i.e. B vitamins (but not B12), C, H • Transport processes in the apical membrane are similar to those described for monosaccharides, amino acids and di- and tri-peptides For example: • Vitamin B9 – the Na+-independent proton-coupled folate transporter 1; FOLT) • Vitamin C – the Na+-dependent vitamin C transporters (SVCT1 and 2) • Vitamin H – the Na+-dependent multivitamin transporter (SMVT)

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