Pufa 2 ppt2 (6)

POLYUNSATURATED FATTY ACIDS: CHEMISTRY, METABOLISM AND CLINICAL SIGNIFICANCE

Presenter: Dr DNYANESH AMLEModerator: Dr T. K. MISHRA

OVERVIEW

Lipids Fatty acids Fatty acid synthesis(in brief)

Unsaturated fatty acid sysnthesis Fatty acid catabolism(in brief)

Unsaturated fatty acid catabolism Essential fatty acids Eicosanoids Trans fatty acids

THE LIPIDS

Heterogeneous group of compounds

• Insoluble in water

• Soluble in nonpolar solvennt

• Eg: fats, oils, steroids, waxes & related

compounds

• Related more by their physical than by chemical

properties

THE LIPIDS

• Important dietary constituents: - Energy provision - Fat soluble vitamins - The essential fatty acids

• storage form of energy (high energy value)

• Thermal insulator

• Non-polar lipids – - electrical insulators in myelinated nerves - rapid propagation of depolarization waves

• Lipoproteins(lipid + protein): - Imp. cellular constituents :cell membrane, mitochondria - Transporting lipids in the blood

CLASSIFICATION

1. Simple lipids: Esters of fatty acids with various alcohols. a. Fats: fatty acids + glycerol. b. Waxes: fatty acids + higher mol wt monohydric alcohols

2. Complex lipids: fatty acid + alcohol + other groups

a. Phospholipids: fatty acid + alcohol + phosphoric acid + N

bases etc.

- Glycerophospholipids: F A + glycerol+ phosphoric acid

- Sphingophospholipids: F A+ sphingosine + phosphoric

acid

b. Glycolipids(glycosphingolipids):F A+ sphingosine +

carbohydrate

c. Other complex lipids: sulfolipids aminolipids.

3. Precursor and derived lipids: fatty acids Glycerol Steroids other alcohols fatty aldehydes and ketone bodies hydrocarbons lipid-soluble vitamins hormones

FATTY ACIDS

• Fatty Acids:Long hydrocarbon chains- varying lengths - varying degrees of unsaturation- terminated with carboxylic acid groups

• Occurrence:- Mainly as esters : Fats & Oils- Unesterified : free fatty acids

• Higher plants & animals predominant C16 and C18 species (palmitic, oleic, linoleic, and stearic acids)

• Fatty acids with <14 or >20 carbon : Uncommon

• Mostly even no.: biosynthesized by the concatenation of C2 units

NOMENCLATURE

The systematic name : Parent hydrocarbon Alkane :Octadecane (18 c)

No double bonds: e oic 18:0, Stearic acid , Octadecanoic acid , CH3(CH2)16COOH

1 double bonds : e enoic 18:1 , n–9 Oleic acid, 9-Octadecenoic acid

CH3(CH2)7CH=CH(CH2)7COOH

2 double bonds: e dienoic 18:2 , n–6 Linoleic acid , 9,12-Octadecadienoic acid CH3(CH2)4(CH=CHCH2)2(CH2)6COOH

3 double bonds : e trienoic 18:3 , n–3 -Linolenic acid , 9,12,15-Octadecatrienoic acid CH3CH2(CH=CHCH2)3(CH2)6COOH

Saturated Fatty Acid Structure

omega end alpha end

degree of saturation: single carbon bond

H H H H H H H H H H H H H H H H H O

H-C--C--C--C--C--C--C--C--C--C--C--C--C--C--C--C--C-C-OH

H H H H H H H H H H H H H H H H H

SATURATED FATTY ACIDS No Double Bonds Acetic acid (CH3-COOH) : first member , -CH2- is

progressively added saturated fatty acids zigzag pattern when extended ( ↓

temp.) highly flexible molecules free rotation about each of their C-C bonds assume a wide range of conformations fully extended conformation steric interference↓

ENEGRY↓ higher temperatures some bonds rotate chain

Shortening So bio-membranes become thinner with temperature

↓↑

computing

Presentation copyright © 2002 David A Bender and some images copyright © 2002 Taylor & Francis Ltd

Saturated fatty acidsno of Cno of C double bondsdouble bonds first C=Cfirst C=C shorthandshorthand

butyricbutyric 44 00 -- C4:0C4:0

caproiccaproic 66 00 -- C6:0C6:0

capryliccaprylic 88 00 -- C8:0C8:0

capriccapric 1010 00 -- C10:0C10:0

lauriclauric 1212 00 -- C12:0C12:0

myristicmyristic 1414 00 -- C14:0C14:0

palmiticpalmitic 1616 00 -- C16:0C16:0

stearicstearic 1818 00 -- C18:0C18:0

arachidicarachidic 2020 00 -- C20:0C20:0

behenicbehenic 2222 00 -- C22:0C22:0

lignocericlignoceric 2424 00 -- C24:0C24:0

Unsaturated Fatty Acids :≥ 1 Double Bonds

(1) Monounsaturated(monoethenoid, monoenoic) : one double bond

(2) Polyunsaturated(polyethenoid, polyenoic) : two or more double bonds.

(3) Eicosanoids:

-derived from eicosa- (20-carbon) polyenoic fatty acids,

- prostanoids (prostaglandins,

prostacyclins & thromboxanes)

- leukotrienes (LTs),

- lipoxins (LXs)

UNSATURATED FATTY ACID

- first double bond: between its C9 and C10 (Δ9-or 9-double bond)

omega end alpha end

One double bond

H H H H H H H H H H H H H H H O

H-C--C--C--C--C--C--C--C--C=C--C--C--C--C--C--C--C--C-OH


Monounsaturated Fatty Acid Structure

computing


no of Cno of C double bondsdouble bonds first C=Cfirst C=C shorthandshorthand

palmitoleicpalmitoleic 1616 11 66 C16:1 C16:1 ωω66

oleicoleic 1818 11 99 C18:1 C18:1 ωω99

cetoliccetolic 2222 11 1111 C22:1 C22:1 ωω1111

nervonicnervonic 2424 11 99 C24:1 C24:1 ωω99

Monounsaturated fatty acids

POLYUNSATURATED FATTY ACIDS (PUFA) :

double bonds at every third C toward the methyl

terminus (-CH=CH-CH2-CH=CH-)

almost never conjugated :Always a –CH2- between

two double bonds

Triple bonds rarely occur

Important classes : n – 3 (or ω– 3) & n – 6 (or ω–6)

fatty acids.

Polyunsaturated Fatty Acid Structure

omega end alpha end

> 2 double bonds

H H H H H H H H H H H H H O

H-C--C--C--C--C--C=C--C--C=C--C--C--C--C--C--C--C--C-OH


Polyunsaturated fatty acids computing


no of Cno of C double bondsdouble bonds first C=Cfirst C=C shorthandshorthand

linoleiclinoleic 1818 22 66 C18:2 C18:2 ωω66

αα-linolenic-linolenic 1818 33 33 C18:3 C18:3 ωω33

γγ-linolenic-linolenic 1818 33 66 C18:3 C18:3 ωω66

arachidonicarachidonic 2020 44 66 C20:4 C20:4 ωω66

eicosapentaenoiceicosapentaenoic 2020 55 33 C20:5 C20:5 ωω33

docosatetraenoicdocosatetraenoic 2222 44 66 C22:4 C22:4 ωω66

docosapentaenoicdocosapentaenoic 2222 55 33 C22:5 C22:5 ωω33

docosapentaenoicdocosapentaenoic 2222 55 66 C22:5 C22:5 ωω66

docosahexaenoicdocosahexaenoic 2222 66 33 C22:6 C22:6 ωω33

Polyunsaturated fatty acids

Unsaturated FA

Unsaturated FA : geometric isomerism around the

axes of double bondsdo not allow rotation

FA double bonds : almost always cis configuration

Rigid 30° bend in the hydrocarbon

Interferes with their efficient packing

Reduced van der Waals interaction

fatty acid melting points with their degree of ↑UNSATURATION

Lipid fluidity with the degree of unsaturation of ↑their component fatty acid residues.

Dietary Effects Of Fatty Acids

Dietary fatty acids regulate plasma LDL-C levels by affecting LDL receptor activity; protein, and mRNA abundance

Cholesterol-raising SFAs (12:0, 14:0, 16:0): decrease LDL receptor activity, protein, and mRNA abundance

Unsaturated fatty acids: increase these variables Mechanism: Dietary modification hepatocyte

membrane fluidity

PUFAs and their various metabolites can act at the level of the nucleus, in conjunction with

nuclear receptors and transcription factors affect the transcription of a variety of genes

peroxisome proliferator-activated receptor (PPAR) hepatocyte nuclear factor (HNF)-4alpha liver X receptor (LXR) sterol-regulatory element binding protein (SREBP) nuclear factor-kappaB (NFkappaB).

critical to the regulation of several key genes of lipid metabolism

PPARα :important role in the regulation of cellular uptake,

activation and β-oxidation of FA natural, preferentially-binding ligands : long chain

unsaturated fatty acids arachidonic acid, linoleic acid, and oleic acid

ligand-activated PPARα binds to PPR Element of DNA & up-regulates transcription of genes involved in lipid catabolism and lipoprotein metabolism

long chain FA sensor : autoregulation of long chain fatty acid metabolism

decreasing tissue content of lipids and minimizing lipotoxicity

may affect body weight improve insulin sensitivity

PPARγ : natural ligands : unsaturated FA (oleate, linoleate,

eicosapentaenoic and arachidonic acids) Adipocytes: PPARγ increases the expression of numerous

genes involved in lipid metabolism and uptake induces adipocyte apoptosis negatively regulates transcription of several genes that

impair insulin action eg. TNFα and leptin ↓proinflammatory cytokines produced by adipocytes and

associated with insulin resistance induce differentiation and apoptosis in various cancer cells

American Heart Association recommends: Total Fat intake < 25-35% of total calories

Saturated FA intake not > 10% of total calories

MUFA intake – 10-15% of total calories

PUFA intake upto 10% of total calories

Ditary reccomendations

Fatty Acids in Common Food Fats

SAFFLOWER OIL

Olive OIL

DE NOVO SYNTHESIS OF FATTY ACIDS(LIPOGENESIS)

Occurs in cytosol liver,kidney, brain, lung, mammary gland,

adipose tissue etc. cofactor : NADPH, ATP, Mn2+ , biotin, and HCO3

(as a source of CO2). Acetyl-CoA PalmitateSYNTHESIS OF FATTY ACIDS

Acetyl CoA is transferred from mitochondria to the cytoplasm, and the reducing potential of NADH is concomitantly converted into that of NADPH by this series of reactions.

Citrate+ 1ATP+1CoA+1H2O → acetyl CoA+1ADP+ Pi+1 oxaloacetate

HOW TO TRNSFER ACETY COA TO CYTOSOL?

Biosynthesis of Fatty Acids

Biosynthesis of malonyl-CoA. (Enz, acetyl-CoA carboxylase.)

Production of Malonyl-CoA : Initial & Controlling Step in Fatty Acid Synthesis

Two steps:(1)carboxylation of biotin involving ATP(2)transfer of the carboxyl to acetyl-CoA to form malonyl-CoA.

Biosynthesis of long-chain FA.Details of how addition of a malonyl residue causes the acyl chain to grow by 2 c atoms.(Cys, cysteine residue; Pan, 4′-phosphopantetheine.)The blocks shown in dark blue:Initially : C2 unit derived from acetyl-CoASubsequently: Cn unit formed in reaction 5.

Microsomal elongase system for fattyacid chain elongation

Monounsaturated FA: Synthesized By Δ9 Desaturase System

Several tissues responsible 1 st double bond introduced:nearly always Δ9

Unsaturated FA in mammals: derived from either palmitoleate (16:1), oleate (18:1), linoleate (18:2), or linolenate (18:3).

No. of C atoms from ω end of a derived unsaturated fatty acid to the nearest double bond identifies its precursor

Stearoyl CoA+ NADH+H+ + O2 oleoyl CoA +NAD+2 H2O→

SYNTHESIS OF POLYUNSATURATED FATTY ACIDS

Higher Animals: Double bonds can be intro-duced at ∆4, ∆5,

∆6, and ∆9 positions additional double bonds are introduced

between the existing double bond and the carboxyl group

linoleic (ω6) or α-linolenic (ω3) acids required for the synthesis of the other members of the ω6 or ω3 families

Must be supplied in the diet

SYNTHESIS OF PUFA :INVOLVES DESATURASE & ELONGASE ENZYME SYSTEMS

Biosynthesis of the ω9, ω6, and ω3 families of polyunsaturated fatty acids. Each step is catalyzed by the microsomal chain elongation or desaturase sys-tem: 1, elongase; 2, ∆6 desaturase; 3, ∆5 desaturase;4, ∆4 desaturase.

FATTY ACID OXIDATION

FATTY ACIDS BETA OXIDATION ACETYL CoA FATTY ACID SYNTHESIS

not the simple reverse entirely different process taking place in a separate compartment FA oxidation: mitochondria allows each process to be individually controlled

& integrated as per requirements

ACTIVATION OF FATTY ACIDS : 1ST STEP

Fatty acids have to be converted to an active intermediate

Only step requiring energy from ATP Acyl-CoA synthetases : found in the ER,

peroxisomes, & inside and on the outer membrane of mitochondria

HOW TO INTRODUSE ACYL-CoA IN MITOCHONDRIA?

Carnitine (β-hydroxy-γ-trimethylammonium butyrate)

CAT

IntermembraneSpace

OUTERMITOCHONDRIALMEMBRANE

Cytoplasmpalmitoyl-CoA

AMP + PPiATP + CoA

palmitate

palmitoyl-CoA

Matrix

INNERMITOCHONDRIALMEMBRANE

CPT-I [2]

ACS[1]

CPT-II

Figure 3 (bottom). Mitochondrial uptake via of palmitoyl-carnitine via the carnitine-acylcarnitine translocase (CAT) (step 5 in Fig. 2).

Matrix


Intermembrane Space palmitoyl-carnitinecarnitine

CoApalmitoyl-CoA

CAT [3]

palmitoyl-carnitineCPT-II

carnitine

CoApalmitoyl-CoA

[4]

CPT-I

CAT

IntermembraneSpace

OUTERMITOCHONDRIALMEMBRANE

palmitoyl-carnitine

CoA

carnitine

Cytoplasmpalmitoyl-CoA

AMP + PPiATP + CoA

palmitate

palmitoyl-CoA

Matrix


[3]

palmitoyl-carnitinecarnitine

CoApalmitoyl-CoA

[4]

CPT-I [2]

ACS[1]

CPT-II

OXIDATION OF UNSATURATED FA: MODIFIED ß-OXIDATION PATHWAY

degraded by the enzymes normally responsible for β-oxidation until either a ∆ 3 -cis -acyl-CoA compound or a ∆ 4 -cis -acyl-CoA com-pound is formed depending upon the position of the double bonds

isomerized (Δ3 cis → Δ 2 -trans-enoyl-CoA isomerase) to the corresponding ∆ 2 -trans –CoA

subsequent hydration and oxidation

Any ∆ 4 -cis -acyl-CoA is then metabolized

Essential fatty acids

Mammals lack the enzymes to introduce double bonds beyond C-9 in the fatty acid chain

Hence cannot synthesize linoleate (18:2 cis-∆9,12) and linolenate (18:3 cis- ∆ 9,12,15)

Essential: must be supplied in the diet because they are required can’t be synthesized by organism itself

starting points for the synthesis of a variety of other unsaturated fatty acids

FUNCTION OF EFAS

Formation of healthy cell membranes Proper development and functioning of the brain

and nervous system Production of hormone-like substances called

Eicosanoids Thromboxanes Leukotrienes Prostaglandins

Responsible for regulating blood pressure, blood viscosity, vasoconstriction, immune and inflammatory responses.

Omega-3

Omega-6

Linoleic Acid (LA): C18:2, n-6 or ω-6. Essential Fatty Acid

Alpha Linolenic Acid (ALA): C18-3, n-3 or ω-3. Essential Fatty Acid

Good source: Flaxseed

Arachidonic Acid (AA): C20:4, n-6 or ω-6.

Good source: Liver, Beef.

Eicosapentaenoic Acid (EPA): C20:5, n-3 or ω-3. Essential Fatty Acid. Good source: Fish oil

Docosahexaenoic Acid (DHA): C22:6, n-3 or ω-3. Essential Fatty Acid. Good Source: Fish oil

ω -3 FATTY ACID

Primarily from fish oil

Also found in canola or soybean oil

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are related

Metabolized to form eicosanoids

ESSENTIAL FATTY ACID- ω -3 (Α -LINOLENIC ACID)

omega end alpha end

1st double bond is located on the 3rd carbon from the omega end

H H H H H H H H H H H H H H H H H O

H-C--C--C=C--C--C =C--C--C=C--C--C--C--C--C--C--C--C-OH

H H H H H H H H H H H

Α-LINOLENIC ACID (ALA)

∆9,12,15-octadecatrienoicacid (18:3n–3, an –3 fatty acid)

Precursor to EPA(∆ 5,8,11,14,17-eicosapentaenoic acid; 20:5n–3) DHA(∆ 4,7,10,13,16,19-docosahexaenoic acid; 22:6n–3)

polyunsaturated –ῳ3 fatty acids Important dietary constituents present in fish oils Improve cognitive function and vision protection against inflammation and

cardiovascular disease

DOCASAHEXANOIC ACID

DHA; ῳ3, 22:6 Source:

Synthesized from α-linolenic acid Fatty Fish oil (albacore, tuna, mackerel,

salmon, sardines)

High conc. In cerebral cortex retinal rod outer segments,testies,sperm

Needed for devlopment of brain and retina

Deficiency of these ῳ –3 PUFA in brain: associated with memory loss and diminished cognitive function,retinitis pigmentosa

ω -6 Fatty Acid

Found in vegetable oils Only need ~ 1 tablespoon a day Arachidonic acid can be made from omega-6 Metabolized to form eicosanoids

Essential Fatty Acid- Omega-6 (linoleic acid)

omega end alpha end

1st double bond is located on the 6th carbon from the omega end

H H H H H H H H H H H H H O

H-C--C--C--C-- C--C =C--C--C=C--C--C--C--C--C--C--C--C-OH


Linoleic acid Abundant in most vegetable oils animals on a fat-free diet : ultimately fatal

condition characterized by poor growth poor wound healing dermatitis

important constituent of sphingolipids functioning as the skin’s water permeability barrier

Omega-6 Vs Omega-3

LINOLEIC 18:2 α-LINOLENIC 18:3 ∆ 6-desaturase

γ-Linolenic 18:3 Octadecatetraenoic 18:4 elongase

Dihomo-γ-linolenic 20:3 Eicosatetraenoic 20:4 ∆ 5-desaturase ARACHIDONIC 20:4 EICOSAPENTAENOIC 20:5 elongaseAdrenic 22:4 Docosapentaenoic 22:5 elongaseTetracosatetraenoic 24:4 Tetracosapentaenoic 24:5 ∆ 6-desaturase Tetracosapentaenoic 24:5 Tetracosahexaenoic 24:6 β-oxidation Docosapentaenoic 22:5 DOCOSAHEXAENOIC 22:6

n-3 fatty acids

Synthesis Of Essential Fatty Acids

n-6 fatty acids Enzymes

Benefits Of Omega-3s

Anti-inflammatory Lower triglyceride and cholesterol levels Cancer prevention Renal maintenance Increase insulin sensitivity Enhance thermogenesis and lipid metabolism Benefits vision and brain function Decrease Skin inflammation Inhibit platelet adhesion Lower PG2s

Benefits of ω -6 Fatty Acids

ω-6 fatty acids with ↑ GLA content may help to

Relieve the discomforts of PMS, endometriosis,

and fibrocystic breasts.

Reduce the symptoms of eczema and psoriasis.

Clear up acne and rosacea.

Prevent and improve diabetic neuropathy.

Dietary EPA (ω3) Dietary linoleic acid (ω6) (essential)

After Babcock et al. Nutrition 16:1116-1118, 2000

Arachidonic acid

(+)(-)

Prostaglandins / Eicosanoids

ProinflammatoryCytokines (IL-1,TNF)

AA

Omega-6 Vs Omega-3

Relative excess omega-6 (PUFA) and a very high omega-6/omega-3 ratio has been shown to promote the pathogenesis of many diseases:-cardiovascular disease

-cancer-Inflammatory and autoimmune diseases

Table - Three 20-carbon FAs and the eicosanoid series derived from them

DietaryFatty Acid

AbbrFormulaω carbons :double bonds

Eicosanoid product series

TXPGPGI

LK Effects

Gamma linolenic acid via Dihomo gamma linolenic acid

GLADGLA

ω-6 18:3ω-6 20:3

series-1 series-3Anti - inflammatory

Arachidonic acid AA ω-6 20:4 series-2 series-4Pro - inflammatory

Eicosapentaenoic acid

EPA ω-3 20:5 series-3 series-5Anti - inflammatory

Omega-6 Vs Omega-3

Differing characteristics ω-3 and ω-6 Essential Fatty Acid Deficiencies

Omega-3 (α-Linolenic Acid) Omega-6 (Linoleic Acid)

Clinical Features

Normal skin, growth, reproductionReduced learningAbnormal electroretinogramImpaired vision

Growth retardationSkin lesionsReproductive failureFatty liver

Biochemical markers

Decreased 18:3 ω-3 and 22:6 ω -3

Increased 22:4 ω-6 and 22:5 ω 7

Increased 20:3 ω-9(only if ω -6 also low)

Decreased 18:2 ω-6 and 20:4 ω-6

Increased 20:3 ω-9 (only if ω -3 also low)

Guthrie H, Picciano, Mary. Human Nutrition. Lipids p128 1995

RECOMMENDATIONS

WHO recommends:

PUFA/ Saturated FA ratio – 0.8 to 1.0

Linoleic acid (ω6)/ Linolenic acid (ω3) ratio- 5 to 10

EFA Deficiency Sign-Symptoms

hemorrhagic dermatitis skin atrophy scaly dermatitis dry skin

weakness impaired vision tingling sensations mood swings edema

high blood pressure high triglycerides hemorrhagic folliculitis hemotologic disturbances (ex: sticky platelets) immune and mental deficiencies impaired growth

EFA Deficiency Sign-Symptoms

Who Are At Risk For Deficiency?

Long-term TPN patients without adequate lipid

Cystic Fibrosis

Low Birth Weight / Premature infants

Severely malnourished patients

Patients on Long-term MCT as fat source

Patients with fat malabsorption

Crohn’s disease

Cirrhosis and alcoholism

At RISK:

Acrodermatitis Enteropathica

Hepatorenal Syndrome

Sjogren-Larsson Syndrome

Multisystem neuronal degradation

Reye’s Syndrome

18:2 linoleic

18:3

20:3

20:4

oleic 18:1

18:2

20:2

20:3

Increased triene/tetraene plasma ratioindicates essential fatty acid deficiency

∆ 9

delta 6 desaturase

Eicosanoids

Arachidonate :major precursor of several classes of signal molecules Eicosanoids

prostaglandins, prostacyclins, thromboxanes, and leukotrienes

A prostaglandin is a 20-carbon fatty acid containing a 5-carbon ring

modified by reductases and isomerases to yield nine major classes of prostaglandins, designated PGA – PGI

called eicosanoids because they contain 20 carbon atoms

Arachidonic Acid (ω6)

cyclooxygenase (COX) lipoxygenase

ProstaglandinsThromboxanes

HPETEHETELeukotrienesLipoxins

Prostacyclin and throm-boxanes : generated by prostacyclin synthase and thromboxane synthase, respectively from nascent prostaglandins

Arachidonate can be converted into leukotrienes by the action of lipoxygenase

local hormones: short-lived alter the activities both of syn-thesizing and of

adjoining cells by binding to 7TM receptors

COX 1 and COX 2

Vane (2002) Science 296:474-475

The major side effect of HYDROGENATION –

Production of TRANS FATTY ACIDS

Cow. Milk and meat from cows and other ruminants contains naturally occurring trans fats in small quantities

TRANS-UNSATURATED FATTY ACIDS

0% Trans Fat is a myth ?

Trans fatty acids

Trans fatty acids are structurally similar to saturated fatty acids

Influences physical properties of cellular membranes

↑ presence of cis = more fluid membrane(B). ↑ presence of trans = less fluid membrane(A). Cis is the most prevalent arrangement in fatty

acids in foods & human body.

Trans Fatty Acid Influence on Metabolic Operations

Influence:

Operation of several lipid enzymes Trans isomers that decrease PG synthesis :

↑linoleic requirement for PG synthesis

Trans isomers devoid of EFA

↓ activity of ∆6 and ∆9 Impair microsomal desaturation and chain

elongation of both linoleic acid and linolenic acid. Gestational development: trans fatty acids cross

the placental barrier AND are also secreted into breast milk.

Trans Fatty Acids: emerged as the most detrimental type of fat relative to increased risk for CHD increasing

plasma LDL-C, TFAs decrease plasma HDL cholesterol (HDL-C) may increase lipoprotein (a)

HEALTH RISK ASSOCIATED WITH TRANS FATTY A

TRANS FATTY ACID

CORONARY HEART DISEASE

COLON & BREAST CANCER

INCREASE INSULIN RESISTANCE- TYPE

2 DM

ALLERGY

ALZIEMER’S DISEASE

OBESITY

Recommendations

Governments around the world to phase out partially hydrogenated oil if trans fat labeling alone doesn't spur significance reduction in their intake

Trans fatty acids consumption < 1% of total daily energy intake.

DENMARK became the first country to introduce laws strictly regulating the sale of many foods containing trans fat - a move which effectively bans partially hydrogenated oil

How Detrimental They Are!

Priming reactions(1) condensation(2) reduction(3) dehydration(4) reduction

2 enzymes involved1. acetyl-CoA carboxylase2. Fatty Acid Synthase Complex

1. acetyl-CoA carboxylase

multienzyme protein variable number of identical subunits, each containing

biotin biotin carboxylase biotin carboxyl carrier protein transcarboxylase regulatory allosteric site.

2. Fatty Acid Synthase Complex

Multi enzyme functional unit dimer comprising two identical monomers each containing all seven enzyme activities of

fatty acid synthase on one polypeptide chain ACP contains the vitamin pantothenic acid of

(4′-phosphopantetheine)

Advantages compartmentalization without permeability

barriers- encoded by a single gene : synthesis of all

enzymes in the complex is coordinated

Fatty acids : synthesized in the cytoplasm acetyl CoA : mitochondria Mitochondria : not readily permeable

acetyl CoA.

HOW TO TRNSFER ACETY COA TO CYTOSOL?

The barrier bypassed by citrate: carries acetyl groups across the inner mitochondrial membrane.

Elongation of FA : Mainly in Endoplasmic Reticulum

Microsomal System elongates saturated and unsaturated fatty acyl-

CoAs (from C10 upward) elongation by two C malonyl-CoA as acetyl donor NADPH as reductant catalyzed by microsomal fatty acid elongase

system of enzymes

Mitochondrial elongation less active acetyl CoA as source of two C units

Main Source of NADPH:PPP

NADPH :donor of reducing equivalents reduction of the 3-ketoacyl & 2,3-unsaturated acyl

derivatives oxidative reactions of PPP: chief source (6) tissues specializing lipogenesis : active PPP both metabolic pathways in cytosol : no barriers

against the transfer of NADPH

Other sources :

Malate malic enzyme (NADP malate dehydrogenase) Pyruvate(8)

extramitochondrial isocitrate dehydrogenase reaction

• Long-chain acyl-CoA (or FFA) will not penetrate the inner membrane of mitochondria

• Carnitine (β-hydroxy-γ-trimethylammonium butyrate)

• widely distributed • particularly abundant in muscle.

ß-OXIDATION OF FATTY ACIDS

two carbons at a time are cleaved from acyl-CoA molecules

starting at the carboxyl end

chain is broken between the α(2)- and β(3)-carbon atoms—hence the name β-oxidation

two-carbon units formed are acetyl-CoA

thus, palmitoyl- CoA forms eight acetyl-CoA molecules.

cyclic reaction sequence generates FADH2 & NADH

“fatty acid oxidase” found in the mitochondrial matrix or inner membrane catalyze

the oxidation is coupled with the phosphorylation of ADP TO ATP

Numbering : Carboxyl carbon C1 C adjacent to carboxyl C no.2,3 & 4 α, β & γ C respectively Terminal methyl carbon ω or n C Δ9 double bond between C 9 and 10 ω9 double bond on the 9th carbon counting from the ω-

carbon

Oleic acid. n − 9 (n minus 9) is equivalent to ω9.

Δ9

ω9

Pufa 2 ppt2 (6)

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