1. METABOLISM OF LIPIDS

2. Things to know
How metabolic oxidation of lipids releases large quantities of energy through production of acetyl-CoA, NADH, and FADH2
How lipids represent an even more efficient way of storing chemical energy

3. Introduction
Triacylglycerols – main storage form of lipids – bond between fatty acid and other molecules can be hydrolysed using lipases enzyme
Phosphoacylglycerols – membrane component – phospholipases
Spider/snake venom – phospholipases- tissue damage and rbc lysis- prevent clot formation

4. Release of fatty acids
[2 Marks]

5. Fatty acid oxidation Begin with activation of molecule
Thioester bond is formed between the carboxyl group of coenzyme A (CoA-SH) – by acyl-CoA synthethase (require ATP)
The activated form of fa – acyl-CoA

6. Β-oxidation
Fatty acids in the from of acyl-CoA molecules are broken down to generate acetyl-CoA, intermediate for TCA cycle
Involve 4 steps

7. For f.a with even number of carbon, the product is acetyl coa.
So for a 18C f.a –
8 cycle
9 AC
C18 – 1AC
C16 – 1AC
C14 – 1AC
C12 – 1AC
C10 – 1AC
C8 – 1AC
C6 – 1AC
C4 – 1AC
C2 – 1AC

8. 17 FADH2 + 35 NADH + 9 GTP = 148 ATP PER ONE
B oxidation products
TCA Cycle
Final products
17 FADH NADH + 9 GTP = 148 ATP PER ONE

9. Comparison One mole of glucose (6C) – Produce 36/38 ATP
3mole of glucose (18C) – 108ATP/114ATP
One mole of f.a – 18C –
Produce already 149 ATP!

10. They don’t need water
Metabolic water is produced during oxidation of f.a
Camel – lipid stored in humps
Kangaroo rats – diets of seed- rich lipid but no water – can live indefinitely without having to drink

11. Ketone bodies
Are produced when excess of acetyl CoA occur arises from B-oxidation
Occur when not enough OAA is available to enter TCA
Happen when organisms has high intake of lipid and low intake of carb in diets
Brain can metabolize ketone bodies (20% requirements)

13. Ketone bodies Acetone can be detected in breath – ketosis
Ketone bodies acidic – their presence overwhelm the buffering capacity
Acetoacetate can be converted to acetyl-CoA to enter TCA
Ketonaemia- rise of ketone bodies in blood above normal level
Ketonuria – when blood level of ketone bodies rises above renal threshold, they are excreted in urine
Ketosis – accumulation of abnormal amount of ketone bodies in tissues and body fluid

14. Causes
starvation- simples form of ketosis occurs – due to depletion of carb reserve, coupled with mobilization of FFA and oxidation to produce energy
In pathologic states:
in DM – clinical and experimental
in some types of alkalosis – ketosis may occur
pregancy toxaemia in sheep and lactating cattle
3. Non pathological states- high fat feeding and severe exercise in the postabsorbtive state

15. Ketosis
Ketosis can be abolished by increasing the metabolism of carb in diet
DM- give insulin
Ketogenic substances – ALL FFA
40% of aa ketogenic
Antiketogenic – all carb, insulin, glucogenic aa, glycerol

16. CHOLESTEROL

17. Cholesterol Membrane structure
Precursor for steroid hormones and bile acids

18. Biosynthesis of cholesterol
Cholesterol is synthesized in many tissues
Mainly in liver and intestine
Acetyl CoA is the precursor
More than half is synthesized in body
Remainder from diet

21. Cholesterol synthesis

22. Regulation of cholesterol synthesis
Is important to prevent accumulation and abnormal deposition of cholesterol in the body
Is primarily regulated by the enzyme HMG-CoA reductase
HMG-CoA reductase is inhibited by cholesterol itself
Fasting inhibit the enzyme – and activate the HMG-CoA lyase to form ketone bodies
The feeding of cholesterol reduces the hepatic biosynthesis of cholesterol
Cholesterol drugs: atorvastatin – inhibit HMG-Coa Reductase

23. Hormonal effect Insulin – increase HMG-CoA reductase actvity
Glucagon and glucocorticoid – decrease the enz activity
Thyroid hormones – stimulate the hormone activity

24. Other factors influence cholesterol level in blood
Dietary fats – diet in saturated fat increase cholesterol level
Dietary cholesterol
Dietary carbohydrates
Hereditity
Blood groups – higher in A and AB than O and B
Dietary fibers- cause excretion of cholesterol and bile acids in feces – reduce serum cholesterol
Exercise – lower cholesterol and increase HDL
Hypolipidaemic drug – block formation of cholesterol

25. Fate of cholesterol Conversion to bile acids - excreted
Conversion to neutral sterols – excreted
Conversion 7-dehydrocholesterol – in skin, UV light will convert it to Vit D
Formation of adrenocorticol hormones
Formation of androgens, estrogens, progesterone

26. Lipid transport and storage
Fats from diets and lipids synthesized must be transported to tissues and organ – utilize and store
They are carried in blood plasma as plasma lipoproteins (macromolecular complexes of specific apolipoprotein)
Diff combination produce diff densities, chylomicrons <VLDL<LDL<HDL
Lipoproteins transport lipid from intestines as chylomicrons and from liver as VLDL to most tissues for oxidation and adipose tissuefor storage
Lipid is mobilized from tissue as free f.a

27. Types of apoproteins HDL – apo-A-I and apo-A-II LDL and LDL– apo-B100
Chylomicrons – apoB48

28. Functions of apoprotein
Make the lipoprotein molecules water miscible (hydrophilic)
May acts as activator or inhibitor of specific enzymes. E.g
Apo-A-I and Apo-A-II act as LCAT activator
apo-C-I and C-II act as activator of lipoprotein lipase
apo-C-III- inhibitor of lipoprotein lipase
apo-B-100 and apo-E- bind with specific receptor on hepatic cells- lead to hepatic uptake

29. Synthesize of chylomicrons and VLDL
CM – in intestinal mucosal cells
VLDL – in liver
LDL- LDL is formed by degradation of VLDL (by losing some if its TG and apo)
Rich in cholesterol and cholesterol esters (bad cholesterol) – transport cholesterol to extrahepatic tissues
Cholesterol delivered by LDL to cells inhibit HMG-CoA reductase – inhibit cholesterol synthesize

30. Major fx
Chylomicrons
Carrier of exogenous TG. Transport mainly TG, PL, cholesterol ester and fat soluble vit from intestinal to liver and adipose tissues. Carrier for dietary lipids
2. VLDL
Carrier of endogenous TG – mainly transports TG synthesized in hepatic cells from the liver to extrahepatic tissues for storage
3. LDL
Transport and delivers cholesterol to extrahepatic tissues
Regulate cholesterol synthesis in extrahepatic tissues – cholesterol delivered by LDL to cells inhibit HMG-CoA reductase – rate limiting enzyme for cholesterol synthesis

31. Fate of LDL
LDL are taken into cell by endocytosis through receptor recognition
The presence of LDL receptor on the cell surface is important for uptake of LDL
LDL is hydrolysed to aa, cholesterol and fa
Free cholesterol – membrane component and inhibit the production of HMG-CoA reductase- suppressed synthesis of cholesterol – and also inhibit the synthesis of receptors – reduce intake of LDL. LDL level in blood increase – deposit as plaques

32. Fate of LDL
Cholesterol not needed for membrane can be stored as fatty acid ester – catalyzed by acyl-CoA : cholesterol acyltransferase (ACAT)
The presence of free cholesterol increases the enzymatic activity of ACAT

33. Catabolism
Lipoprotein lipases hydrolyzes TG from chylomicron to produce free fa and glycerol
The released fa are taken by cells
Lipoprotein lipases activity declines in adipocytes during starvation - reduce uptake of lipid by adipose tissue
Starvation enhances Lipoprotein lipases activity in cardiac and muscle – to oxidize more fa

34. HDL
Is synthesized in liver cells and in intestinal mucosa cells. Apo-A , Apo-E and Apo-C as the carrier
Strip off the cellular cholesterol from peripheral cells and muscles of arteries
Activates the LCAT- esterification of cholesterol to HDL
Transported to liver- catabolism

35. HDL
Provide Apo-C and Apo-E to VLVL and chylomicrons to be acted upon lipoprotein lipase
Stimulate synthesis of prostacylin synthesis by endothelial cells – inhibits platelet aggregation and prevent thrombus formation
Helps in removal macrophages from arterial wall

36. Bile acids Bile helps in digestion and absorption of lipids
Stored in gallbladder
Bile acids -Steroid acids found in bileFx
Lowering surface tension – emulsification of fats
Accelerate the action of pancreatic lipase
Form micelles with fa-helps absorption
Aid in absorption of fat soluble vit

37. Bile acids Keep cholesterol in solution
In GB, cholesterol is solubilized and held in micelles with the help of conjugated bile salts and phospholipids
Bile salts content decreased – imbalance of micelles- cholesterol leak out – crystallize and form gall stones
Gall stones – formed due to precipitation of cholesterol

38. Excess LDLs invade tissues of the artery and become modified
Excess LDLs invade tissues of the artery and become modified. The modified molecule stimulate the production of adhesion molecules, sticking out into the blood stream. Attract monocytes and T cells to the site.
Monocytes mature into active macrophages and produce many inflammatory molecules to digest LDL
Fat filled macrophages (foam cells) – earliest form of atherosclerotic plaque
Atherosclerosis

39. Atherosclerosis
Inflammatory molecules promote growth of plaque and form a fibrous cap over the lipid core. The fibrous cap seal off the fatty core from the blood
Foam cells weaken the cap by secreting digesting matrix molecules. If the weakened cap ruptures, tissue factors display on the foam cells will interact with clot promoting element in the blood causing a clot (thrombus)

40. Familial cholesteralaemia – defective gene that code for receptor – develop atherosclerosis earlier

41. TASK
DISCUSS ON HYPERCHOLESTROLAEMIA IN ANIMAL – what animal involve? Due to what? Diet? Genetic defect?
Discuss on ketosis in animal – explain the mechanism
Discuss