1. The Small Intestine: Absorption 2 Lecture 5 Professor John Peters

2. Lipid Absorption (1)  Transfer between mixed micelles and the apical membrane of enterocytes entering by the cell by passive diffusion Free Fatty acids and monoglycerides 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

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

4. 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: o be stored o secreted unaltered in bile o oxidised to bile salts

5. 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

6. Absorption of Ca 2+  Occurs by passive (i.e. paracellular; whole length of small intestine) and active (i.e. transcellular; mainly duodenum and upper jejunum) transport mechanisms  With [Ca 2+ ] in chyme  5 mM absorption is mainly active  Active Ca 2+ absorption is regulated by 1,25- dihydroxyvitamin D 3 (calcitriol) and parathyroid hormone (increases 1,25- dihydroxyvitamin D 3 synthesis) Ca 2+- ATPase (PMCA1) – expression increased by 1,25-dihydroxyvitamin D3 Sodium/calcium exchanger (NXC1) Ca 2+ channel (TRPV6) – expression increased by 1,25- dihydroxyvitamin D3 Ca 2+ (high lumenal Ca 2+ ) Ca 2+ (low lumenal Ca 2+ ) Ca 2+ - calbindin-D Ca 2+ 3Na + Ca 2+ (high lumenal Ca 2+ )

7. Absorption of Iron  Iron – important constituent of haemoglobin, myoglobin, many enzymes  12-15 mg ingested daily – only 3-10 % absorbed (female more than male) Divalent metal transporter 1 (DMT1) Ferroportin (negatively regulated by the hormone hepcidin released from liver when body iron levels are high) – major control on iron absorption Haem carrier protein 1 Haem Fe 3+  Fe 2+ Fe 2+  Fe 3+ (Vit C) Haem oxidase Fe 2+ Apoferratin + Ferratin (storage form of iron) Fe 2+ + Transferrin Transferrin-Fe 2+ e.g. haemoglobin synthesis

8. 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 B 12 ), C, H o Vitamin C – the Na + -dependent vitamin C transporters (SVCT1 and 2)  Transport processes in the apical membrane are similar to those described for monosaccharides, amino acids and di- and tri-peptides o Vitamin H – the Na + -dependent multivitamin transporter (SMVT) For example: o Vitamin B 9 – the Na + -independent proton-coupled folate transporter 1; FOLT)

9. Absorption of Vitamin B 12 (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 B 12 ingested in food Salivary glands secrete haptocorin Stomach acid releases vitamin B 12 from food Haptocorin binds vitamin B 12 released in stomach Stomach parietal cells release intrinsic factor Pancreatic proteases digest haptocorin in small intestine, vitamin B 12 released Vitamin B 12 binds to intrinsic factor in small intestine Vitamin B 12 -intrinsic factor complex absorbed in terminal ileum by endocytosis

10. Summary  After this lecture and personal study, you should be able to  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 Ca 2+ and iron are regulated processes  Outline the mechanisms that underlie the absorption of water- and fat- soluble vitamins  Explain why the absorption of vitamin B 12 is a special case that requires a complex series of events