Lipid

METABOLISM
Cyberjaya University College of Medical Sciences
Prof Dr Noor
Aini AH

LIPID DIGESTION &

ABSORPTION

 Dietary Lipids
-

20-40% calorie intake

Mainly >90% - triacylglycerol (TG)
- 16-18 C, mixture
Others phosphoglycerides,
cholesterol ester, cholesterol
- Fat solid at room temp
- animal source
- 40-60% saturated FA

Oil liquid at room temp

- plant source
- 80-90% unsaturated FA
- coconut oil mainly saturated
FA 12-14C
- olive oil 79% oleic acid
(monounsat)
- safflower oil, corn oil 76% linoleic
acid
(polyunsat)
- fish oil (salmon) 25-35% -3
(ecosapentaenoic acid)

-glycerol is the backbone to which 3

fatty acyl residues R1, R2, R3 are
attached to C1,C2,C3 resp.
-monoacylglycerols 1- monoacylg, 2monoacylg-diacylglycerol 1,2- or 1,3diacylg metabolic intermed.-1,2diacylg 2nd messenger

Digestion of Lipids
Stomach
- lingual & gastric lipases
- hydrolyze short & medium chain FA
- active in children
- cows milk - short & medium chains
- food fr stomach to duodenum stim:
- cholecystokinin
contraction of gallbladder +
release of pancreatic juice
- hepatocrinin bile secretion by
liver

 Small intestines
- Pancreatic juice bicarb + pancreatic
enzymes pancreatic lipase
- cholesterol esterase
- phospholipase A2
- Colipase - cofactor
- Bile from gall bladder
Bile bile acid, phospholipids,
cholesterol,
salt, H2O, bilirubin etc
- peristalsis help to break lipids

Emulsification of Lipids
-occurs in duodenum bile
-Bile acid & phosphatidylcholine
(found in bile)
micelles aggregate formed in aq
sol by subst composed by both polar
& non polar groups eg
phosphatidylcholine amphiphatic
mixed micelles dispersed diet
lipids for action of lipases

Micelles

Hydrolysis of TG
-pancreatic lipase
-Long chain FA 16-18C
-R3, R1
-Colipase activates pancreatic lipase
- anchors bile salt to lipase

Pancreatic lipase

TG 1,2-diacylglycerol + FA
1,2-diacylglycerol 2-monoacylglycerol + FA
TG 2-monoacylglycerol + 2FA

Phospholipid lysoPL + FA
Phospholipase A2

Cholesterol Ester
Cholesterol + FA
cholesterol esterase

Absorption of Lipid
-FA + 2-monoacylglycerol + cholesterol + PL +
other diet lipid eg fat soluble vitamins
packaged in micelles microvilli lipids
absorption passive diffusion
Jejunum & ileum
-Bile salts reabsorbed to portal circ ileum
-Short & medium chain FA (C4-12) absorbed
directly into intes epit cell intracell lipase FA
+ glycerol portal system
- cows milk, synthetic form - chronic pancreatitis

- In int cell FA resynthesise to TG

- 2-Monoacylglycerol + FACoA Diacylglycerol +
CoA
Diacylglycerol + FACoA TG + Co A

- Cholesterol + FA Cholesteol ester

- LysoPL + FA PL
- All lipids + apoprotein B48 Chylomicron

- TG + CE + PL + C + other lipids +
apoproteins chylomicrons

 Lipid malabsorption
- Chronic pancreatitis - lipases
- Bile duct obstruction cholelithiasis, ca
head of pancreas
- Chronic liver disease liver cirrhosis
Steatorrhoea bulky, fatty stool

 Apoproteins
- proteins that form lipoproteins
- in chylomicrons ApoB-48 (most imp)
- ApoAI, A2, A4
- ApoB-48 only present in chylomicrons
- Apo CII & ApoE transferred fr HDL
- Apo CII activates lipoprot lipase
(LPL)
- ApoE recognise by liver cells recept

Lipid Transport
Lipids are insoluble in aqueous
materials such as blood plasma.
To transport these insoluble substances
within the lymph and blood, they are
complexed with proteins to form
lipoprotein.

Lipoprotein

5 classes of plasma
lipoproteins exist in
humans:

 range in size from

10 to 1000nm
composed of a
hydrophobic core
containing
cholesteryl esters,
triglycerides, fatty
acids and fatsoluble vitamins
the surrounding
hydrophilic layer is
composed of
various
apolipoproteins,
phospholipids and
cholesterol.

General structure of a plasma

lipoprotein

Types of lipoproteins
1. Chylomicrons
2. VLDL (very low density lipoprotein)
3. IDL (intermediate density
lipoprotein)
4. LDL (low density lipoprotein)
5. HDL (high density lipoprotein)
Principal lipids carried by above
lipoproteins are
Triglycerides
Cholesterol and cholesteryl esters
Phospholipids

COMPOSITION OF
LIPOPROTEINS

CHYLOMI
Triglycerides
90%
Cholesterol & CE 5%
Phospholipids
3%
Apolipoprotein
2%

VLDL
60%
20%
15%
5%

LDL
8%
50%
22%
20%

HDL
5%
25%
30%
40%

Density increases with decreasing

TG content or increasing protein

Apoproteins
- proteins in lipoproteins
- in chylomicrons ApoB-48 (most imp)
-in VLDL / LDL - Apo B100
- HDL Apo CII & ApoE
transfer to Chylomicron, VLDL
- Apo CII activates lipoprot lipase (LPL)
- ApoE recognise by liver cells recept
Apo B100 recognise by LDL receptor at
endothelium

METABOLISM OF CHYLOMICRON
CHYLOMICRON

5%
90%

3%

TRIGLYCERI
CHOLESTER

5%
2%

PHOSPHOL
APOLIPOPR

Structure of chylomicron

48

Chylomicrons
-synthesised in intestinal mucosal cells -carry
dietary lipids
- contain apoB-48
- secreted into lymphatic system by
exocytosis.
- carried via lymphatic system- thoracic duct
into
systemic blood circulation.
Deficiency in apo B
accumulation of lipids in intestinal epithelial
cells &
leads to hypolipoproteinemia

Lymphatic system to
Thoracic duct and
finally opens at left
Subclavian vein(blood)

Main function
-transport exogenous lipid (from diet)
from intestine to liver and extrahepatic
tissue: muscle, adipose tissue
In blood circulation
- + apo CII, apo E from HDL
- TG fatty acid + glycerol by LPL
- apo CII activate LPL
- FA adipose tissue storage
muscle - oxidation
( FA + albumin )
Glycerol liver (+ glycerol kinase)

Chylomicron remnant
TG liver
- receptor recognise apo E
-Endocytosis
-Hepatic lipase, lisosom hydrolyses
chylomicron
TG, CE, C, PL
- In liver - utilized
- reassembled with new
apoproteins and
endogenous lipids to form

Transfer of Apo E and Apo CII

from HDL to chylomicron

In circulation chylomicron receives apoE

and apoC-II from HDL

Deficiency in lipoprotein lipase

or apoC-II accumulation of
triglycerides in plasma (Type I
hyperlipidemia) or (Familial
hyperchylomicronemia)

Chylomicron

METABOLISM OF VLDL (VERY LOW

DENSITY LIPOPROTEIN)
VLDL

20%

TRIGLYCERI
20%

60%

15%

CHOLESTER
PHOSPHOL

5%

APOLIPOPR

VLDL Synthesis
In liver - some of the lipid components
brought by chylomicron remnants
(exogenous)
- lipid components synthesised by liver
(endogenous lipids)
- + apoprotein B100
- secreted by exocytosis
Function
- carry both exogenous and endogenous
lipids from liver to extrahepatic tissues.

Synthesis of VLDL in Liver

In Blood circulation
- VLDL receives apoE and apoC-II
from HDL.
- Cholesterol esters from HDL is also
transferred to VLDL by Cholesteryl
ester transfer protein ( CETP).

 As the VLDL circulate through blood

circulation,
they are acted by lipoprotein lipase and
triglycerides are degraded.
Fatty acids and glycerol are released.
Remnant VLDL is called IDL
IDL will further lose some TG as well as ApoC
and apoE to form Low density lipoprotein
(LDL)
So the conversion of VLDL to IDL and finally
to Low density lipoprotein (LDL) occurs in
circulation

Very low density lipoprotein (VLDL)

Very low density lipoprotein (VLDL)

METABOLISM OF LDL (LOW DENSITY

LIPOPROTEIN)
LDL

22%

50%

CHOLESTER

42%

PHOSPHOL
20%

8%

TRIGLYCERI

APOLIPOPR

LDL
- Contains high percentage of cholesterol and
cholesterol esters.

Function
- LDL carry cholesterol to extrahepatic tissues.
Receptors of LDL on cell surfaces recognise
apoB-100 in LDL and internalises by
endocytosis.
- Internalised LDL is acted by lysosomal enzymes
Results in release of cholesterol into cell
- Increases activity of ACAT (acyl CoA cholesterol
acyltransferase)
Converts cholesterol to cholesterol ester
storage in the cells

-When the plasma LDL is high - down

regulation of cell surface receptors
- Up regulation occurs when cell
increases receptors to internalise more
LDL can also by simvastatin or
pravastatin drugs
- Cholesterol released inhibits HMG CoA
reductase and decreases de novo
synthesis by the cell
Defective LDL receptor results in
increased plasma LDL called Type II
hyperlipidemia (Familial
hypercholesterolaemia)

Low density lipoprotein (LDL)

Elevated LDL can undergo oxidation

oxidised LDL
taken by macrophages (scavenger
receptor SR-A) that later forms the foam
cells
- SR-A is not down regulated.
-These cells will be located below the
endothelial layer and cause injury to the
site that ultimately causes formation of
atherosclerotic plaque.
-This will narrow the blood vessel lumen
-increases blood pressure
-cardidovascular disease MI, stroke

METABOLISM OF HDL (HIGH DENSITY

LIPOPROTEIN)
HDL

30%
25%

CHOLESTER

70%
40%

5%

TRIGLYCERI
PHOSPHOL
APOLIPOPR

Synthesis
-liver and small intestine
-Released to circulation by exocytosis
-Disc shape nascent HDL
-PL, C, apo E apo CII, apo A1
In blood
- + cholesterol fr extra hep tissue - free
cholesterol received is esterified by the
enzyme LCAT Lecithin cholesterol
acyltransferase. CE

-CE are carried to liver by HDL where it is

degraded and the cholesterol can be

converted to bile acids excretion.
- Some of the cholesterol esters are
transferred to VLDL
Function
- removing excess free cholesterol from
extrahepatic tissues.
- act as reservoir of apoE and apoC-II.

High density lipoprotein (HDL)

 People with high HDL are resistant

to the development of
atherosclerosis
Premenopausal women have
higher HDL level than men or
postmenopausal women
Normal level

> 1.4 mmol/L

Lipoprotein (a) Lp(a)

- almost like LDL but have apo(a)
attached apo B-100.
- genetically determined
- diet trans fatty acids increase
Lp(a)
- oestrogen decreases LDL & Lp(a)
- Lp(a) slows breakdown fibrin
degradation

FATTY ACID SYNTHESIS

Fatty acids ( FA ) are synthesised actively

by
the
liver.
These
are
called
endogenous fatty acids
Fatty acids are synthesised from acetyl
CoA when there is caloric excess.
Dietary EXCESS carbohydrate (GLUCOSE)
is the major source for the synthesis of
FA
Other than glucose, amino acids and other
sources of acetyl CoA can contribute
towards FA synthesis.

FA synthesised can exist as free FA or as

esters, mainly as triacylglycerol.
Others
like
phospholipids
contain FA.

cholesterol
esters,
and sphingolipids also

Triacyglycerol is also called triglycerides

( TG ) is the major storage of lipids.
TG is stored in adipose tissue.

FATTY ACID SYNTHESIS

Carbohydrates
(Glucose)

Amino acids Lipids

Acetyl CoA

CO2
Acetyl CoA carboxylase ATP
ADP

Malonyl CoA
NADPH

Fatty acid synthase complex

NADP+

Palmitic acid

Glucose are converted to pyruvate

(glycolysis) which then enter the
mitochondria where it forms acetyl CoA.
Since acetyl CoA cannot cross
mitochondrial membrane it condenses
with oxaloacetate to form citrate Citrate
shuttle
Acetyl CoA + Oxaloacetate

Citrate

Citrate is transported out into cytoplasm

Citrate lyase

Citrate

Acetyl CoA + oxalocaetate

Citrate in cytosol is converted to Acetyl CoA

and Oxaloacetate

TG synthesis

Fatty Acid synthesis

1. Acetyl CoA + oxaloacetate
2. Citrate Shuttle
3. Conversion of Acetyl CoA to Malonyl
CoA
4. Elongation reactions at FA synthase
complex

CO2

Acetyl CoA Acetyl CoA

Malonyl CoA

carboxylase

Malonyl CoA serves as the immediate

donor of the 2-carbon unit which is
added sequentially to lenghthen the
fatty acid chain by the fatty acid
synthase.
Acetyl CoA carboxylase is the rate
limiting enzyme of FA synthesis.

Fatty acid synthase complex

Fatty acid synthase catalyses the synthesis of
fatty acids in elongation of fatty acid chain
until forming palmitate (16 C ).
Initially acetyl CoA provides the -methyl carbon
of palmitate.
Malonyl CoA provides the 2-carbon units that are
added to the growing fatty acyl chain.

Fatty acid synthase complex

Palmitate and other fatty acids can

also be desaturated to form
unsaturated fatty acids
Finally these fatty acids are
activated to fatty acyl CoA which
interact with glycerol 3-phosphate
to form triacylglycerol and packed
into VLDL and secreted into
circulation.

REGULATION OF FATTY ACID

SYNTHESIS
Allosteric modification
Acetyl CoA carboxylase is
activated by citrate which causes
it to polymerise.
Inhibited by palmitoyl CoA.

Regulation of Acetyl CoA carboxylase

1.Stimulated
by citrate
2.Inhibited by
Palmitoyl
CoA
3.Inhibited
glucagon &
stimulated
by insulin

However, humans cannot synthesise

the following polyunsaturated fatty
acids due to lack of specific
enzymes:
Linoleic acid ( 18: 9,12)
Linolenic acid ( 18:9,12,15 )
The above fatty acids are called
ESSENTIAL fatty acids

Triacylglycerol formed in adipose tissue will be

stored.
Triacyglycerol synthesis is activated by insulin.
Triacylglycerol formed in liver is packed into
VLDL and secreted into circulation.
VLDL as it passes through capillary, it is acted
by lipoprotein lipase which hydrolyses the
triacylglycerol to fatty acids and glycerol.
Fatty acids are taken up by peripheral tissue
to generate energy through -oxidation and
electron transport chain.

Fatty acids taken up by adipose tissue

forms triacyglycerol and are stored.
Excessive storage can cause obesity
Obesity can be determined from BMI
(Body Mass Index)
= Wt / (Ht)2 . Normal ~ 20 - 25
BMI Value > 30 indicates obesity.

abnormal lipid metabolism leads to

obesity risk factor DM type II,
cardiovascular
diseases,
osteoarthritis,
gall
stone
formation and others.

High fat with saturated fatty acids

High fiber, high fish protein and PUFA

LIPOLYSIS & OXIDATION

Lypolysis
Breakdown of TG FA + glycerol
Adipose tissue
Hormone sensitive lipase
Provide FA fasting, strenuous
exercise,stress
- Hormones glucagon, adrenaline
-

- FA released + albumin tissue (muscle)

oxidation
- Glycerol liver gluconeogenesis

Regulation
- Fasting blood glucose glucagon
c-AMP lypolysis
- Stress/strenuous exercise adrenaline

c-AMP lypolysis
- Fed state blood glucose Insulin/
glucagon lypolysis

Fatty Acid Oxidation ( oxidation)

- Aerobic
- FA catabolism CO2, H2O + energy
(ATP + heat)
- Sources : - diet carried by
lipoprotein (LPL)
- lipolysis
- Most tissues except brain,
erythrocytes
- Main energy source

- oxidation
- In mitochondria
- From carboxyl end ie C3/
2 C fragment cut off from FA chain
each cycle to produce acetyl-CoA
consecutively
Products:
Acetyl-CoA Kreb cycle
NADH, FADH2 Resp chain ATP

3 important steps
1. FA activation Fatty acyl-CoA
- in cytosol
2. Transport Fatty acyl-CoA into
mitochondria
- carnitine shuttle
3. Reactions that takes place in oxidation
- oxidation
- hydration
- oxidation
- cleavage

FA activation
Long chain FA are activated by thiokinase
present at the outer membrane of
mitochondria
Long chain fatty acid
Thiokinase

ATP

CoASH (coenzyme A)

AMP

Fatty acyl CoA

Fatty acyl CoA then carried into
mitochondria by carnitine shuttle

-Oxidation of fatty acids

4 steps are repeated until all carbons of an
even chain fatty acids are oxidised to
acetyl CoA.
Each set of reaction produces 1 NADH, 1
FADH2 1molecule of acetyl CoA and an
acyl CoA that is 2 carbons less than the
original.
Thus, palmitoyl CoA with 16 carbons will
undergo 7 sets of - oxidation to
complete its conversion to acetyl CoA.

-Oxidation of even chain fatty acid

Palmitoyl CoA
CH3 CH2 CH2 CH2 CH2 CH2 CH2
CH2
CH2
CH2
CH2
CH2
CoAS~C CH2 CH2 CH2
O

Acetyl CoA + Acyl CoA + NADH + FADH2

Regulation of fatty acid

oxidation:
-- oxidation is regulated by the
levels of ATP and NADH
- glucose - Malonyl CoA an
intermediate in fatty acid
synthesis inhibits carnitine
acyltransferase I. This prevents
oxidation during synthesis.
-Fasting lipolysis FA
oxidation acetyl Co A & NADH
inhibit pyruvate dehydrogenase
save glucose

HUNGER state
FA
glucose

FA-CoA
pyruvate

Acylcarnitine

(-)
(-)

Acetyl CoA

PDH
Acetyl CoA

FED state
Glucose

Pyruvate

PDH
Trans I

Acetyl CoA

Malonyl CoA

FA

FA

FA CoA

(-) Acylcarnitine

Acylcarnitine
(-)
-oxidation

Oxidation of odd chain fatty acids

Fatty acids with odd number of carbons
also oxidised by - oxidation.
However, in the last set of reaction it will
yield an acetyl CoA and a 3carbon
propionyl CoA.
Propionyl CoA is converted to succinyl
CoA

Energy Comparison
Glucose ( MW = 180 g/mol)
Lauric acid (12:0) (MW= 200 g/mol)
Glucose
Consider 1 mol
32 mol ATP/180 g = 0.18 mol ATP/g
glucose
Lauric Acid
Consider 1 mol
78 mol ATP/200 g = 0.39 mol ATP/g
lauric acid
Dietary Values
4 Cal/g for carbohydrates

METABOLISM OF KETONE BODIES

Excess breakdown of fatty acids lead
to the formation of ketone bodies;
-acetoacetate, - hydroxybutyrate
and acetone.
During;
High fat and low carbohydrate diet
Fasting / Starvation
Uncontrolled diabetes mellitus

Ketogenesis or ketone formation

occurs mainly in the liver
- in mitochondria
As increased fatty acid oxidation
produce high concentration of
acetyl CoA.
Less oxaloacetate to form citrate
FA synthesis
This causes accumulation of acetyl
CoA which reacts as follows:

Acetyl CoA + Acetyl CoA

Thiolase

CoA

Acetoacetyl CoA
HMG CoA synthetase

Acetyl CoA

Hydroxymethylglutaryl CoA ( HMG CoA )

HMG CoA lyase
Acetoacetate

Synthesis of
Acetoacetate

HMG-CoA
synthetase
stimulated during
fasting

Formation of - hydroxybutyrate
and acetone.

These ketone bodies are released into

circulation where they are utilized by
extrahepatic tissues to generate energy.
- Acetone excreted via lungs

Utilization of ketone bodies to

generate energy

NAD
Hydroxybutyrate+
NADH

Hydroxybutyrate dehydrogenase

Acetoacetate
Succinyl CoA
Succinyl CoA transferase

Thiolase

Succinate

Acetoacetyl CoA
CoA

Acetyl CoA + Acetyl CoA

During starvation BRAIN adapts to use

ketone bodies to produce energy.
During fasting HMG CoA synthetase is
induced by high glucagon: insulin ratio.
Liver cannot generate energy from
ketone bodies since Succinyl CoA
tranferase are not sufficiently present .
In uncontrolled diabetes, excessive
ketone bodies are produced causes
ketonemia leading to ketonuria.

Starvation and ketone

bodies

CHOLESTEROL
METABOLISM

Cholesterol
Ester

Cholesterol Ester
-FA chain replaces OH C3

-Usually unsaturated FA
-oleic acid cholesteryl oleate
-linoleic cholesteryl linoleate

Ester Formation
1. In tissue liver, intestine, adrenal
cortex, arterial wall
ACAT
- acyl Co A + cholesterol
cholesterol ester + Co Ash
2. In plasma
LCAT
- phosphatidylcholine + cholesterol
cholesterol +
lysophsphatidylcholine

Sources of cholesterol
-diet 40%
-De novo synthesis 60%
-Diet 200-300mg/day
-Digestion & absorption small
intestine
chylomicron

Synthesis of Cholesterol
-liver, intestine, adrenal cortex, ovary,
testis
-In cytosol
-From acetyl CoA CHO, lipid, amino
acid
-Acetyl Co A from mitochondria
cytosol via citrate shuttle

5 major steps
1. Acetyl CoA 3-hydoxy-3-methyl
glutaryl CoA (HMGCoA)
2. HMGCoA mevalonate
3. Mevalonate isoprene based
molecule isopentenyl
pyrophosphate (IPP), with loss of
CO2
4. IPP squalene
5. squalene lanosterol
cholesterol

Regulation of Cholesterol synthesis Mainly by regulation of HMG CoA reductase

1. Feedback inhibition
- cholesterol cellular level - activity,
synth
- mevalonate
2. Covalent modification
- active in dephosphorylated state
- inactive in phosphorylated state
3. Hormonal
- insulin dephospho of HMGCoA reductase
- glucagon phoshorylation
- insulin - synthesis of HMG CoA reductase

4. Enzyme degradation - cholesterol in

cell degradation

5. Supression of LDL receptor down

regulation by cholesterol itself
6. Circadian rhythm - midnight (max 6
hrs after dark)
- at noon ( min 6
hrs after light)

Maintaining normal Blood Cholesterol

Level
1. Diet - cholesterol intake - 10-15%
- no intake - 40%
- sat FA - synthesis cholesterol
- unsat FA - synth cholesterol
Mech Unsat FA upregulates LDL receptor
- palmitate inhibits bile acid
synthesis
- Low cal diet - CHO, Lipid - acetyl CoA
2. Exercise Use of FA for energy
- HDL
3. Stop smoking smoking HDL

Drug therapy if above fails

1. Mevinolin, Mevastatin, Lovastatin:
- HMG-CoA reductase inhibitors.
- increased cellular uptake of LDLs,
since the intracellular synthesis of
cholesterol is inhibited and cells are
therefore dependent on extracellular
sources of cholesterol.
2. Cholestyramine or colestipol (resins):
- nonabsorbable resins that bind bile
acids - not
reabsorbed by the liver but excreted.
- Reduce feedback inhibiton bile acid
synthesis

Familial Hypercholesterolaemia
- Defect in LDL receptor
cellular cholesterol no inhibition
to HMGCoA reductase - syntheis
cholesterol further blood
cholesterol
- Atherosclerosis at young age

Synthesis of Bile Acids

-In liver
-From cholesterol
-Cholesterol 7-hydroxylase
-1 bile acid synthesized in liver cholic acid
chenodeoxycholic
-2 - deoxycholic acid, lithocholic acid formed
in intestine
-95% reabsobed enterohepatic circulation

Conjugation
-in liver
-With glycine or taurine
-cholic acid, glycocholic or taurocholic
-chenodeoxycholic glycochenodeoxydholic or
taurochenodeoxycholic
secreted to the intestine via common bile duct or
stored in gallbladder

In intestine
-Deconjugation remove glycine & taurine
-Then cholic acid deoxycholic acid
-chenodeoxycholic lithocholic acid
95%reabsorbed via intrahepatic ciculation.
Regulation
-Cholesterol 7-hydroxylase
-Product inhibition, palmitate
- excretion bind to resin (cholestyramine) inhibition
to 7-hydroxylase

Eicosanoids
-20 C polyunsaturated fatty acids
-stored in membrane PL
Omega-6 class of essential FA
-Eicosatrienoic acid (20:3-6), eicosatetraenoic acid
(20:4 -6) from linoleic acid (18:2 -6)
Omega-3 class of essential FA
-eicosapentanoic acid (20:5-3)- derived from linolenic
acid (18:3 -3)

20:4 -6 arachidonic acid

-most important
-From membrane phospholipid by phospholipase A2 from phosphatidylcholine and phospholipase C from
phosphatidylinositol
PL A2
-Phosphatidylcholine arachidonic acid
PLC

DAG lipase

-Phosphatidylinositol 1,2 DAG MAG +

arachidonic acid
-PLA2 is activated by calcium ion

Ecosapentaenoic acid (EPA) 20:5 3

-Synthesized from linolenic acid (18:3 3)
-High in fish oil
-Precursor for series-3 prostaglandin, series-5
leukotrienes
-Reduce the extent of inflammatory response
induced by the series-2 PG, series-4 leukotrienes
-Reduce cholesterol, TG level in hyperTG
patients

Eicosanoid metabolism
-From arachidonic acid
1.Cyclooxygenase pathway
-endothelial cells
Produces prostaglandin and thromboxanes
2.Lipoxygenase pathway
-neutrophil leukocytes
produces leukotrienes, hydroxyeicosatetraenoic acids
(HETEs), lipoxins
-Platelets both cyclooxygenase and lipoxygenase paths
3.Cytochrome P450 forms epoxides

Prostaglandin
-Ecosanoid 20C
-Synthesized from arachidonic acid (20:4 -6)
cyclooxygenase pathway
-Contain cyclopentane ring, C8,9,10,11,12
-7types of rings A,B,D,E,F,G,H,I series differ in
the substituent on the cyclopentane ring
-PGE1,PGE2,PGE3 1,2,3 means no of double bond
in the HC chain
-2-series primary PGs PGD2,PGE2,PGF2,PGI2 &
thromboxane A2 - widely dist in body

Prostanoic acid
parent structure for PG

Pathways for eicosanoid formation

ARACHIDONIC ACID
Cyclooxygenase
PG
G
PGH22

Lipoxygenase

HPETE

Prostaglandins
Thromboxanes
Leukotrienes
HETE Lipoxins

Cytochrome P

Epoxides

Biosynthesis of prostaglandin
Formation arachidonic acid
-Stimulation by inflammatory stimuli such cytokines,
bradykinin, adrenaline, thrombin release Ca2+ activates PL A2 hydrolyse arachidonic from
membrane PL
-Inhibited by corticosteroids
-Activation of PL C

Cyclooxygenase pathway
Arachidonic acid prostaglandin endoperoxide
(PGH2) by Cyclooxygenase
1.

-Stimulated by inflammatory stimuli

-Self inactivation act 15-30s prevents
overproduction of PG
-Can be inhibited by NSAID aspirin, indomethacine
etc
2. PGH2 PGE2, PGI2 by PG synthase
3. PGH2 tromboxane A2 by TXA2 synthase

Functions:
-Mediates physiolgical response
- inflammatory response
- production of pain and fever
- regulation of blood pressure
- regulation of blood coagulation
- induction of labour
- reduce gastric acid secretion
- sleep promoting substance PGD2

Lipoxygenase Pathway
-3 types of Lipoxygenase 5, lipoxygenase, 12 & 15
1. A.A hydroxyperoxy-eicosatetaenoic acid
(HPETEs)
- short lived
2. HPETEs leukotrienes, lipoxins,
hydroxyeicosatetraenoic acids (HETEs)

LEUKOTRIENES
-Lipooxygenase pathway
-Contains 3 conjugated double bonds
-LTA4, LTB4, LTC4, LTD4, LTE4
-Brochoconstriction
-Increase vascular permeability
-Attraction & activation of leucocytes
inflammatory response
-SRS-A (LTC4, LTD4, LTE4)

Thank you