1. Metabolism of dietary lipids

2. Metabolism of Dietary Lipids
Biochemistry II
What is digestion?
Digestion is the breakdown of large molecules into smaller soluble molecules, which can pass through the wall of the gut into the blood.

3. Metabolism of Dietary Lipids
Biochemistry II
>90% of dietary lipids = Triacylglycerol (TAG)
The remainder consists of phospholipids, cholesterol, cholesterylester and free fatty acids.
Lipases can digest dietary lipids into:
free fatty acids (FFAs)
2-monoacylglycerol
cholesterol
lysophospholipids

4. Problems facing digestion and transport of lipids
Metabolism of Dietary Lipids
Biochemistry II
Problems facing digestion and transport of lipids
The insolubility of lipids in water represents a unique problem for the digestion and transport of dietary lipids:
On the one hand, enzymes that act on lipids are soluble proteins.
On the other hand, lipids and their degradation products, must be transported through aqueous compartments not only within the cell but also in the blood and tissue spaces.

5. How can the problem of insolubility of lipids in water be overcome?
Metabolism of Dietary Lipids
Biochemistry II
How can the problem of insolubility of lipids in water be overcome?
Emulsification
Mechanical mixing due to peristalsis
Detergent properties of bile salts

6. What is peristalsis? Peristalsis is the progressive wave of
Metabolism of Dietary Lipids
Biochemistry II
What is peristalsis?
Peristalsis
is the progressive
wave of
contractions
and relaxations
of a tubular
muscular system, by which the contents are
forced through the system

7. Metabolism of Dietary Lipids
Biochemistry II
Bile acids (bile salts)
Bile acids (bile salts) are amphipathic cholesterol derivatives with detergent properties.
They are secreted into the gallbladder after being formed in liver, and enter the intestine via the bile duct, where they contribute to the digestion of fats and fat-soluble vitamins.

8. Metabolism of Dietary Lipids
Biochemistry II
Bile acids (bile salts)
Bile acids emulsify lipid globules into smaller micelles, leading to an increase in the surface area accessible to digestive enzymes.
They assist in solubilizing lipid breakdown products and preventing them from coalescing.

9. Bile acids (bile salts) / Emulsification
Metabolism of Dietary Lipids
Biochemistry II
Bile acids (bile salts) / Emulsification

10. Bile acids (bile salts)
Metabolism of Dietary Lipids
Biochemistry II
Bile acids (bile salts)
Secretion of bile salts and cholesterol into the bile by liver is the only mechanism of cholesterol excretion.
Most cholesterol and bile acids are reabsorbed in the small intestine and returned to the liver via the portal vein and may be re-secreted. This process is referred to as the enterohepatic cycle.
Examples for Substances that interrupt the enterohepatic cycle are :
Synthetic resins (Cholestyramine) , as well as soluble fiber (fruit pectin), that bind bile acids and/or cholesterol, prevent absorption/re-absorption.
The drug ezetimibe acts on cells lining the lumen of the small intestine and inhibit absorption of cholesterol.

11. Processing of dietary lipids in the small intestine / TAG
Metabolism of Dietary Lipids
Biochemistry II
Processing of dietary lipids in the small intestine / TAG
Pancreatic lipase is an esterase, which preferentially removes the fatty acids at carbons 1 and 3 The primary products are therefore 2-MAGs and FAs.
The Enzyme is abundant in a high concentration and is highly efficient  malabsorption observed only in case of severe pancreatic deficiency(e.g. cystic fibrosis)

12. Processing of dietary lipids in the small intestine / TAG
Metabolism of Dietary Lipids
Biochemistry II
Processing of dietary lipids in the small intestine / TAG
Colipase anchors the lipase at the interface of micelles
Colipase is secreted by the pancreas as a procolipase, which is activated in the intestine by trypsin.
Orlistat, inhibits gastric and pancreatic lipases and decreases thereby fat absorption, resulting in loss of weight.

13. Metabolism of Dietary Lipids
Biochemistry II
Mechanism of interfacial activation of triacylglycerol lipase in complex with colipase

14. Metabolism of Dietary Lipids
Biochemistry II
Processing of dietary lipids in the small intestine / Cholesteryl ester

15. Processing of dietary lipids in the small intestine / Phospholipids
Metabolism of Dietary Lipids
Biochemistry II
Processing of dietary lipids in the small intestine / Phospholipids
PLA2
Phospholipase A2 (PLA2) is a proenzyme, which needs first to be activated by trypsin.
PLA2 removes one fatty acid from carbon 2 of phospholipid, leaving a lysophospholipid, which is a detergent.
Lysophospholipase removes the remaining fatty acid at C1, leaving a glycerylphosphoryl base, that might be excreted in the feces, further degraded, or absorbed.

16. Substrate binding to phospholipase A2 A hypothetical model
Metabolism of Dietary Lipids
Biochemistry II
Substrate binding to phospholipase A2 A hypothetical model
No conformational change upon interfacial binding

17. Control of lipid digestion
Metabolism of Dietary Lipids
Biochemistry II
Control of lipid digestion
Low pH of the chyme entering the intestine
Presence of lipids and digested proteins
Secretion of cholecystokinin (peptide hormone) by the
Secretion of secretin
(small peptide hormone
mucosa of the lower
produced by intestinal cells)
duodenum and jejunum
Contraction of gallblader 
release of bile
Release of the digestive enzymes of the pancreas
Decrease of gastric motility
Cause liver and pancreas to release a solution
containing bicarbonate  optimal pH for digestive pancreatic enzymes

18. Dietary Lipids Are Transported in Chylomicrons
In the intestinal mucosal cells, the TAG are re-synthesized from FAs and monoacylglycerols.
Then packaged into chylomicrons.

19. Intestinal lumen Intestinal mucosa
Dietary TGs
Bile salt
Other lipids & proteins
micelles
H2O
Pancreatic Lipase
Chylomicrons
Lymph system
FAs
TGs
Monoglyceroles
Intestinal lumen
Intestinal mucosa
Monoglyceroles
FAs
lipoprotein lipases
Storage in adipose tissue
TGs
b-oxidation in muscle

20. Metabolism of Dietary Lipids
Biochemistry II
The Brush border membrane of the enterocytes = Site of absorption for degraded lipids in mixed micelles.
The membrane has an unstirred water layer.
Due to the hydrophilic surface of the micelles  easier transport of lipids through the unstirred water layer
Aassistance of mixed micelles is not required for absorption Fas (C< 12).

21. Intestinal fatty acid–binding protein (I-FABP)
Metabolism of Dietary Lipids
Biochemistry II
Intestinal fatty acid–binding protein (I-FABP)
The Poorly soluble FAs are
sequestered from the cytosol of enterocytes by being bound with intestinal fatty acid binding protein (I-FABP) .
This process protects cells from their detergent effect.

22. Re-synthesis of triacylglycerol and cholesteryl esters
Metabolism of Dietary Lipids
Biochemistry II
Re-synthesis of triacylglycerol and cholesteryl esters
Lipids absorbed by the enterocytes migrate to the ER (place where biosynthesis of complex lipids occurs).
FAs are first activated by means of fatty acyl CoA synthetase (Thiokinase)
2-MAGs are converted to TAGs by the enzyme complex, TAG synthase; 2 enzyme activities:
Acyl CoA:monoacylglycerol acyltranferase
Acyl CoA:diacylglycerol acyltranferase

23. Re-synthesis of triacylglycerol and cholesteryl esters
Metabolism of Dietary Lipids
Biochemistry II
Re-synthesis of triacylglycerol and cholesteryl esters
Short and medium-chain fatty cids are not converted to their CoA derivatives.
They are transported into the liver using albumin.
Chol is esterified to a fatty acid by means of acylCoA : cholesterol-acyltransferase.

24. Secretion of lipids from enterocytes
Biochemistry II
Metabolism of Dietary Lipids
Secretion of lipids from enterocytes
The newly synthesized TAGs and cholesterylesters
are very hydrophobic, and aggregate in an aqueous environment.
Packing these lipids into a lipid particle surrounded by a thin lipid layer of Pl and Chol and a single protein molecule
 chylomicron 
Solubility
Chylomicrons are released by exocytosis from enterocytes into the lymphatic system and reach thereafter the
blood circulation.
Coalescence Stability

25. Use of dietary lipids by the tissues
Biochemistry II
Metabolism of Dietary Lipids
Use of dietary lipids by the tissues
Chylomicrons TAGs are broken down in free FAs and glycerol by lipoprotein lipase primarily in the capillaries of skeletal muscle and adipose tissues
FAs may directly enter adjacent cells or adipocytes or be transported in the blood in association with serum albumin until taken up by other cells.

26. Use of dietary lipids by the tissues
Biochemistry II
Metabolism of Dietary Lipids
Use of dietary lipids by the tissues
Most cells can oxidize FAs to produce energy.
Adipocytes can also re-esterify free FAs to produce TAGs.
Chylomicron remnants bind to receptors on the liver and are then endocytosed.
Glycerol can be converted into glycerol 3-phosphate, which can enter either glycolysis or gluconeogenesis

27. Glycerol formed by lipolysis is absorbed by the liver where it enters glycolysis or gluconeogenesis.
phosphatase

28. Noncarbohydrate precursors of glucose
Triglycerols
glycerol
Fatty acids
Dietary & muscle
proteins
Amino acids

29. Metabolism of Dietary Lipids
Biochemistry II
Processing of dietary lipid in the stomach
Lingual lipase and gastric lipase (secreted by the gastric mucosa) degrade TAGs (C<12).
These lipases are of importance for neonates and for patients suffering from cystic fibrosis.

30. Lipid malabsorption
Lipid malabsorption, resulting in increased lipid (including the fats soluble vitamins and essential fatty acids) in the feces (that
is, steatorrhea),
can lipid
be caused by
disturbances in absorption
digestion
and/or
Such disturbances can resulted from several conditions, including CF (causing poor digestion) and shortened bowel (causing decreased absorption).