1. Copyright Do not remove this notice COMMONWEALTH OF AUSTRALIA
Copyright Regulation
WARNING
This material has been reproduced and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act).
The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.
Do not remove this notice

2. Fat and Cholesterol Metabolism

4. Dietary Fat Lipogenesis is not very active in people on a Western diet
Lipogenic enzyme expression is down-regulated by fat consumption
Most of our fat comes from the diet ~100g/day
Most fat in white adipose tissue will have come from dietary fat and not de novo lipogenesis
Fat is hydrophobic
Problems for digestion and transport
Digestive enzymes need fat to be in an emulsion
Fat needs to be carried around the bloodstream within lipoproteins

5. Formation of Emulsions
Molecules have hydrophilic and hydrophobic characteristics
amphiphilic
amphipathic
Phospholipids in cell membranes
As is the phosphatidic acid and lysolecithin in salad dressing
Amphiphilic molecules act as detergents
emulsify fat into tiny ‘particles’
micelles

6. Bilayers and Micelles
In both structures, polar heads are facing the aqueous environment while the hydrophobic tails are buried in the core
Micelles can also be formed using bile salts

7. Fat Digestion Pancreatic Lipase
Fat is contained in the core of micelles that formed with bile salts
Churning of dietary fat with bile salts in the intestine
Chyme
Emulsion
Easy for lipase to interact with
Pancreatic Lipase
Hydrolyses fat into FA and glycerol
Plus mixture of mono- and di-acyl glycerols

8. FIGURE 17-1 Processing of dietary lipids in vertebrates
FIGURE 17-1 Processing of dietary lipids in vertebrates. Digestion and absorption of dietary lipids occur in the small intestine, and the fatty acids released from triacylglycerols are packaged and delivered to muscle and adipose tissues. The eight steps are discussed in the text.

9. Bile Salts Produced in the liver Made from cholesterol
Cholesterol itself it not amphiphilic enough to be a detergent - needs modification by addition of polar groups
Stored in the gall bladder
After digestion of fat
Reabsorbed and taken back to the liver
Via hepatic portal vein

10. Bile Salts
Polar groups are added to cholesterol to make it more amphiphilic
The only way to get rid of cholesterol is to make them into bile salts (chol cannot be oxidised)

11. Undigested Fat If gall bladder is blocked by gall stones
no bile salts secreted  less fat digestion  lower calorie intake
Inhibitors of fat digestion as weight-loss drugs
Orlistat (brand name Xenical)
Listed side effects include
oily spotting; orange colored oil in your stool;
gas with oily discharge;
an urgent need to go to the bathroom; an inability to control bowel movements, an increased number of bowel movements.

12. Olestra Olestra (Olean) is a fat substitute FA attached to sucrose
Not attacked by lipases
Olestra will passes through gut undigested
Carries with it fat soluble vitamins
D, E, K need to be added as supplements
See anti-Olestra sites
eg.

13. Lipoproteins Mixture of phospholipid and Apoproteins
Apoproteins role - Enzymes, Structural, Docking
Different types of lipoproteins characterised by size and by types of apoproteins
First lipoproteins made by intestinal cells
Chylomicrons
Enter lymphatic system
Contains fat and cholesterol esters

14. FIGURE Lipoproteins. (a) Structure of a low-density lipoprotein (LDL). Apolipoprotein B-100 (apoB-100) is one of the largest single polypeptide chains known, with 4,636 amino acid residues (Mr 513,000). One particle of LDL contains a core with about 1,500 molecules of cholesteryl esters, surrounded by a shell composed of about 500 more molecules of cholesterol, 800 molecules of phospholipids, and one molecule of apoB-100.

15. FIGURE 21-38 Synthesis of cholesteryl esters
FIGURE Synthesis of cholesteryl esters. Esterification converts cholesterol to an even more hydrophobic form for storage and transport.

16. FIGURE 21-40 Lipoproteins and lipid transport
FIGURE Lipoproteins and lipid transport. (b) Blood plasma samples collected after a fast (left) and after a high-fat meal (right). Chylomicrons produced after a fatty meal give the plasma a milky appearance.

17. Delivery of Fat to Tissues
Insulin stimulates LPL
Also increases the supply of glycerol 3-phosphate for re-esterification
Chylomicrons interact with tissues through lipoprotein lipase (LPL)
LPL is on the surface of cells
Fat in chylomicrons hydrolysed to fatty acids and glycerol

18. FIGURE 21-40a Lipoproteins and lipid transport
FIGURE 21-40a Lipoproteins and lipid transport. (a) Lipids are transported in the bloodstream as lipoproteins, which exist as several variants that have different functions, different protein and lipid compositions (see Tables 21-1, 21-2), and thus different densities. Dietary lipids are packaged into chylomicrons; much of their triacylglycerol content is released by lipoprotein lipase to adipose and muscle tissues during transport through capillaries. Chylomicron remnants (containing largely protein and cholesterol) are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissue by VLDL. Extraction of lipid from VLDL (along with loss of some apolipoproteins) gradually converts some of it to LDL, which delivers cholesterol to extrahepatic tissues or returns to the liver. The liver takes up LDL, VLDL remnants (called intermediate density lipoprotein, or IDL), and chylomicron remnants by receptormediated endocytosis. Excess cholesterol in extrahepatic tissues is transported back to the liver as HDL. In the liver, some cholesterol is converted to bile salts.

19. Fate of FAs and Chylomicrons
Fatty acids from chylomicron after lipolysis can be:
Burnt in the heart and muscle
Stored in WAT (hopefully not elsewhere)
Build up of fat in the muscle associated with Type 2 diabetes
FAs in WAT mainly re-esterified  FAT
Re-esterification needs glycerol phosphate (Glyc3P)
Glyc3P is made by glycolysis & glyceroneogenesis
As fatty acids stripped out, chylomicron gets smaller
And more cholesterol rich
Form chylomicron remnants

20. Liver: Import/Export Chylomicron remnants taken up by liver
Endocytotic process
Internal digestion of remnants
Release of cholesterol into liver
Liver assembles VLDL from fat and cholesterol esters
The fat could have been made by lipogenesis
VLDL excreted into the blood stream

21. VLDL & LDL - Transport of Cholesterol
LPL in peripheral tissues works on VLDL just as it did on chylomicrons
 VLDL becomes fat depleted
Remaining particle (LDL) relatively cholesterol rich
Tissues take up LDL through LDL receptor
Endocytotic process like chylomicron remnants.
This is how cholesterol is delivered to the tissues

22. FIGURE 21-42 Uptake of cholesterol by receptor-mediated endocytosis.

23. FIGURE 21-40a Lipoproteins and lipid transport
FIGURE 21-40a Lipoproteins and lipid transport. (a) Lipids are transported in the bloodstream as lipoproteins, which exist as several variants that have different functions, different protein and lipid compositions (see Tables 21-1, 21-2), and thus different densities. Dietary lipids are packaged into chylomicrons; much of their triacylglycerol content is released by lipoprotein lipase to adipose and muscle tissues during transport through capillaries. Chylomicron remnants (containing largely protein and cholesterol) are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissue by VLDL. Extraction of lipid from VLDL (along with loss of some apolipoproteins) gradually converts some of it to LDL, which delivers cholesterol to extrahepatic tissues or returns to the liver. The liver takes up LDL, VLDL remnants (called intermediate density lipoprotein, or IDL), and chylomicron remnants by receptormediated endocytosis. Excess cholesterol in extrahepatic tissues is transported back to the liver as HDL. In the liver, some cholesterol is converted to bile salts.

24. LDL Receptors Tissues express LDL receptors ONLY if want cholesterol
Nearly all of our cells can make cholesterol themselves
 when cells have enough cholesterol, they will stop making cholesterol & stop expressing LDL receptor
Macrophages take up LDL without control
 produce foam cells  form plaques
HMG-CoA reductase is the rate limiting step in making cholesterol
Can be inhibited by statins

25. Reverse Cholesterol Transport

26. FIGURE 21-40a Lipoproteins and lipid transport
FIGURE 21-40a Lipoproteins and lipid transport. (a) Lipids are transported in the bloodstream as lipoproteins, which exist as several variants that have different functions, different protein and lipid compositions (see Tables 21-1, 21-2), and thus different densities. Dietary lipids are packaged into chylomicrons; much of their triacylglycerol content is released by lipoprotein lipase to adipose and muscle tissues during transport through capillaries. Chylomicron remnants (containing largely protein and cholesterol) are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissue by VLDL. Extraction of lipid from VLDL (along with loss of some apolipoproteins) gradually converts some of it to LDL, which delivers cholesterol to extrahepatic tissues or returns to the liver. The liver takes up LDL, VLDL remnants (called intermediate density lipoprotein, or IDL), and chylomicron remnants by receptormediated endocytosis. Excess cholesterol in extrahepatic tissues is transported back to the liver as HDL. In the liver, some cholesterol is converted to bile salts.

27. TABLE 21-1 Major Classes of Human Plasma Lipoproteins: Some Properties

28. TABLE 21-2 Apolipoproteins of the Human Plasma Lipoproteins

29. FIGURE 21-39b Lipoproteins
FIGURE 21-39b Lipoproteins. (b) Four classes of lipoproteins, visualized in the electron microscope after negative staining. Clockwise from top left: chylomicrons, 50 to 200 nm in diameter; VLDL, 28 to 70 nm; HDL, 8 to 11 nm; and LDL, 20 to 25 nm. For properties of lipoproteins, see Table 21-1.

30. FIGURE 21-33 Summary of cholesterol biosynthesis
FIGURE Summary of cholesterol biosynthesis. The four stages are discussed in the text. Isoprene units in squalene are set off by red dashed lines.

31. FIGURE 21-34 Formation of mevalonate from acetyl-CoA
FIGURE Formation of mevalonate from acetyl-CoA. The origin of C-1 and C-2 of mevalonate from acetyl-CoA is shown in pink.

32. FIGURE Regulation of cholesterol formation balances synthesis with dietary uptake. Glucagon promotes phosphorylation (inactivation) of HMG-CoA reductase; insulin promotes dephosphorylation (activation). X represents unidentified metabolites of cholesterol that stimulate proteolysis of HMG-CoA reductase.

33. Ways to Reduce Blood Cholesterol
Reduce consumption of cholesterol
Less meat, dairy products
But intake of cholesterol is very small vs stores
Inhibit absorption of cholesterol from gut
Phytosterols as competitive inhibitors?
 reabsorption of bile salts by using resins that bind to bile salts
liver has to make more bile salts from cholesterol
Inhibit cholesterol synthesis by using “statins” which inhibit HMG-CoA reductase
Consume polyunsaturated fatty acids
high saturated fat results in  HDL and LDL

34. Cholesterol Flux Total cholesterol in body ~140g
~1g of cholesterol enters the body each day from diet
But only 0.5 g absorbed
~18g bile salts secreted into gut per day
and 17.5g is reabsorbed per day
the net loss of bile salt is very little (~0.5 g/day)
So amount absorbed = amount lost as bile salts
A reduction in intake will most likely be met by an increase in endogeous choleseterol synthesis
But compare the store size to the intake
140 g to 0.5 g
vs carbohydrate for which the store size and intake are similar magnitude
vs fat – intake (100 g) < store (15,000 g)

35. Importance of Cholesterol
Cholesterol is important for:
Steroid hormone synthesis
Regulating membrane fluidity
Membrane fluidity is important for:
Structural integrity
Receptor/enzyme activity

36. Membrane with Saturated FA
No double bond in FA
Membrane crystalline

37. Membrane with Unsaturated FA
Unsaturated FA  Kinks
Membrane is less crystalline, more fluid and more permeable

38. Cholesterol & Membrane Fluidity
Cholesterol “fine tunes” membrane fluidity