The Small Intestine: Absorption 2Lecture 5

Professor John Peters

Lipid Absorption (1) 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 acidsMonoglycerides

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

Lipid Absorption (2) – Chylomicron Lipid Absorption (2) – Chylomicron Formation Formation

Phospholipid synthesis

Apolipoprotein(ApoB-48)

Cholesterolesters

Central lacteal

Carried in lymph vessels to systemic

circulation (subclavian vein) via the thoracic

duct

Exocytosis

Monoglyceride

Free fatty acid

Triglyceride synthesis

Chylomicron

Nascentchylomicron

Endoplasmic reticulum

Lipid Absorption (3) – Chylomicron Lipid Absorption (3) – Chylomicron Processing 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 storedo secreted unaltered in bileo oxidised to bile salts

Lipid Absorption (4) – Cholesterol Lipid Absorption (4) – Cholesterol Absorption 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

Absorption of CaAbsorption of Ca2+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 [Ca2+] in chyme 5 mM absorption is mainly active

Active Ca2+ absorption is regulated by 1,25-dihydroxyvitamin D3 (calcitriol) and parathyroid hormone (increases 1,25-dihydroxyvitamin D3 synthesis)

Ca2+-ATPase (PMCA1) – expression increased by 1,25-dihydroxyvitamin D3

Sodium/calcium exchanger (NXC1)

Ca2+ channel (TRPV6) – expression increased by 1,25- dihydroxyvitamin D3

Ca2+

(high lumenal Ca2+)

Ca2+

(low lumenal Ca2+)

Ca2+-calbindin-D

Ca2+

Ca2+

3Na+

Ca2+

(high lumenal Ca2+)

Absorption of IronAbsorption 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

Fe3+Fe2+

Fe2+ Fe3+

(Vit C)

Haem oxidase

Fe2+

Apoferratin+

Ferratin(storage form of iron)

Fe2+

+Transferrin

Transferrin-Fe2+

e.g. haemoglobin synthesis

Absorption of VitaminsAbsorption 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

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 B9 – the Na+-independent proton-coupled folate transporter 1; FOLT)

Absorption of Vitamin BAbsorption of Vitamin B1212 (cobalamin) (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

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 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