5 Lipid Metabolism

LipidMETABOLISM

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, 2-monoacylg-diacylglycerol – 1,2- or 1,3-diacylg metabolic intermed.-1,2-diacylg – 2nd messenger

Digestion of Lipids

• Stomach - lingual & gastric lipases - hydrolyze short & medium chain FA - active in children - cow’s 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

- cow’s 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:

General structure of a plasma lipoprotein

• range in size from 10 to 1000nm

• composed of a hydrophobic core containing cholesteryl esters, triglycerides, fatty acids and fat-soluble vitamins

• the surrounding hydrophilic layer is composed of various apolipoproteins, phospholipids and cholesterol.

Types of lipoproteins1. Chylomicrons2. 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 areTriglyceridesCholesterol and cholesteryl estersPhospholipids

COMPOSITION OF LIPOPROTEINS

CHYLOMI VLDL LDL HDLTriglycerides 90% 60% 8% 5%Cholesterol & CE 5% 20% 50% 25%Phospholipids 3% 15% 22% 30%Apolipoprotein 2% 5% 20% 40%

Density increases with decreasing TG content or increasing protein content

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 receptApo B100 – recognise by LDL receptor at endothelium

METABOLISM OF CHYLOMICRON

CHYLOMICRON

90%

5% 3%

2%

5%

TRIGLYCERI

CHOLESTER

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 VLDL.

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

60%

20%

15%

5%

20%

TRIGLYCERI

CHOLESTER

PHOSPHOL

APOLIPOPR

VLDL SynthesisIn 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

8%

50% 22%

20%

42%

TRIGLYCERI

CHOLESTER

PHOSPHOL

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

5%

25%30%

40%

70%

TRIGLYCERI

CHOLESTER

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 cholesterol esters, phospholipids and sphingolipids also contain FA.

Triacyglycerol is also called triglycerides ( TG ) is the major storage of lipids.

TG is stored in adipose tissue.

FATTY ACID SYNTHESIS

Carbohydrates Amino acids Lipids(Glucose)

Acetyl CoA

Acetyl CoA carboxylase

Malonyl CoA

Fatty acid synthase complex

Palmitic acid

CO2

ATP

ADP

NADPH

NADP+

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 Acetyl CoA + oxalocaetate Citrate lyase

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

Acetyl CoA Malonyl CoA

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.

Acetyl CoA carboxylase

CO2

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 obesityObesity can be determined from BMI (Body Mass Index) = Wt / (Ht)2 . Normal ~ 20 - 25BMI 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 & β 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 steps1. FA activation Fatty acyl-CoA - in cytosol2. Transport Fatty acyl-CoA into mitochondria - carnitine shuttle3. Reactions that takes place in -oxidation - oxidation - hydration - oxidation - cleavage

FA activationLong chain FA are activated by thiokinase present at the

outer membrane of mitochondriaLong chain fatty acid

Thiokinase ATP

CoASH (coenzyme A)

Fatty acyl CoAFatty acyl CoA then carried into mitochondria by

carnitine shuttle

AMP

-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 CoACH3 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2

CH2CH2 CH2CH2

CoAS~C– CH2 – CH2 – CH2

Acetyl CoA + Acyl CoA + NADH + FADH2

O

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

(-) (-) PDH

Acetyl CoA Acetyl CoA

FED state

Glucose FA

Pyruvate FA CoA PDH (-) Acylcarnitine Trans I Acetyl CoA Acylcarnitine

Malonyl CoA (-) -oxidation

FA

Oxidation of odd chain fatty acidsFatty 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– 9 Cal/g for fats and oils

METABOLISM OF KETONE BODIESExcess breakdown of fatty acids lead to the

formation of ketone bodies;-acetoacetate, - hydroxybutyrate and acetone.During;High fat and low carbohydrate diet Fasting / StarvationUncontrolled diabetes mellitus

Ketogenesis or ketone formation occurs mainly in the liver

- in mitochondriaAs increased fatty acid oxidation produce high

concentration of acetyl CoA.Less oxaloacetate to form citrate – FA synthesisThis 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 lyaseAcetoacetate

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 energyHydroxybutyrate

Hydroxybutyrate dehydrogenase

Acetoacetate

Succinyl CoA transferase

Acetoacetyl CoAThiolase

Acetyl CoA + Acetyl CoA

NAD+

NADH

Succinyl CoA

Succinate

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 – control of gene expression

4. Enzyme degradation - cholesterol in cell degradation

5. Supression of LDL receptor – down regulation by cholesterol itself6. Circadian rhythm - midnight (max 6 hrs after dark) - at noon ( min 6 hrs after light)

Maintaining normal Blood Cholesterol Level1. 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 CoA2. Exercise – Use of FA for energy - HDL3. 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 - cholesterol is converted to bile acids to maintain a steady level in circulation.

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

PGH 2

Lipoxy-genase

HPETE

Cytochrome P450

Epoxides

Prostaglandins Thromboxanes

Leukotrienes HETE Lipoxins

PGG2

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

1. Arachidonic acid prostaglandin endoperoxide (PGH2) by Cyclooxygenase

-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)

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