METABOLISM OF LIPIDS
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
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 lysisprevent clot formation
Release of fatty acids
[2 Marks]
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
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
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
B oxidation products
TCA Cycle
Final products
17 FADH2 + 35 NADH + 9 GTP = 148 ATP PER ONE
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!
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
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)
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
Causes
1. starvation- simples form of ketosis occurs – due
to depletion of carb reserve, coupled with
mobilization of FFA and oxidation to produce
energy
2. 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
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
CHOLESTEROL
Cholesterol
• Membrane
structure
• Precursor for
steroid hormones
and bile acids
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
Cholesterol synthesis
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
Hormonal effect
• Insulin – increase HMG-CoA reductase actvity
• Glucagon and glucocorticoid – decrease the
enz activity
• Thyroid hormones – stimulate the hormone
activity
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
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
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
Types of apoproteins
• HDL – apo-A-I and apo-A-II
• LDL and LDL– apo-B100
• Chylomicrons – apoB48
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
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
Major fx
1. 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
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 reductasesuppressed synthesis of cholesterol –
and also inhibit the synthesis of
receptors – reduce intake of LDL. LDL
level in blood increase – deposit as
plaques
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
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
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 LCATesterification of cholesterol to
HDL
• Transported to livercatabolism
• 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
HDL
• 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
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 micellescholesterol leak out –
crystallize and form gall stones
• Gall stones – formed due to
precipitation of cholesterol
Bile acids
• 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
• 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)
Atherosclerosis
• Familial
cholesteralaemia –
defective gene that
code for receptor –
develop atherosclerosis
earlier
TASK
• DISCUSS ON HYPERCHOLESTROLAEMIA IN
ANIMAL – what animal involve? Due to what?
Diet? Genetic defect?
• Discuss on ketosis in animal – explain the
mechanism
• Discuss