Metabolisme Lipid (2012)

7/23/2019 Metabolisme Lipid (2012)

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LIPID METABOLISM

Abdul Salam M. SofroFaculty of Medicine YARSI

ni!er"ity



#a"u"$Nn. G seorang mahasiswi usia 20 thcurhat ke pamannya seorang dokterberat badannya cenderung naik terus.

G mengatakan kalau pagi tidakmakan nasi, cuma makan roti 2 lapisisi mentega, jam, telur rebus dan

segelas susu skim. Jika siang makanmi ayam dan malam baru makan nasiatau mi goreng. Di kampus menjelangsore suka makan French ries !potatochips" atau beli bakso.



#eaching aims

• #o highlight utili$ation and storage

o energy in lipid orm and• understand the indi%idual

biochemical pathways o lipid

metabolism !general, lipidbiosynthesis and lipid catabolism"



&cope o lipid metabolism

• 'iosynthesis o atty acids

• ()ydation o atty acids*ketogenesis

• +F - icosanoids /etabolism



Introduction

• s biomolecule, lipids areimportant or structure, obtain

and storage o energy• #heir characteristics are

nonpolar and hydrophobic

• /ostly contain or deri%ed romatty acids



• &tored in the orm otriacylglycerol more ecient -1uantitati%ely more important

compared with carbohydratestorage as glycogen

• /ore important unctions such

as* integrity o al%eoli,solubili$ation o nonpolarcompounds, metabolic processes

etc.



Food

Carbohydrate Lipid Protein Others (Nucleic acids,

water, minerals,vitamins etc.)

Lumen of G tract

!ucosal cells

"i#estion of $%G to&

#lycerol ' fatty acidseesterification of $%G from &

#lycerol ' fatty acids

Lympatic system and

then blood circulation

Or#ans ' tissues

*iosynthesis of fatty acids

O+ydation of fatty acids& eto#enesis

-% ' /icosanoids !etabolism

Cholesterol synthesis, transport ' e+cretion

Lipid transport ' stora#e!etabolism of acyl#lycerols ' sphin#olipids

Lipid transport



Food*

arbohydra

te3rotei 4ipidNucleic

acid(therswater

G5tract

/ucosal cells 'ody6organ cells %a"te

a%um oris(esophagus%entriculus

4ymph6

lacteal

'lood





Lipids are a major source of energyduring rest and exercise. Approximately

half of the lipids –stored as triglycerides–

that are used for energy come fromadipose tissue with the other half from

intramuscular stores. There are several

steps in the mitochondrial oxidation oflipids that begin with the mobilization of

the triglycerides



Metaboli"m of dietarytriacyl&lycerol"

• #hree primary sources o atty acids*

–Dietary triacylglycerols

– #riacylglycerols synthesi$ed in the li%er

– #riacylglycerols stored in at cells

Fatty acids must be deli%ered to cells

where 78o)ydation occurs *• 4i%er• 9eart

• &celetal muscles



Li'id Metaboli"m in animal"

• Fats are hydrophobic a system is needed or theirabsorption beore

they can be metaboli$ed

4ipase in the stomach and sali%a are

not %ery e:ecti%e/ost at ends up in duodenum assmall

globules'ile is used at this point to aid in















(Lipogenesis)





Bio"ynt(e"i" of fatty acid")cont.*

• Fatty acid synthesis or lipogenesis may%ary between indi%iduals

• 9ighly acti%e e)tramitochondrialsystem is responsible or the completesynthesis o palmitate rom acetyl8o!in the cytosol"

• nother system or atty acidelongation is also present in li%erendoplasmic reticulum



#he main pathway or de no%olipogenesis

• 3resent in many tissues, including li%er,kidney, brain, lung, mammary gland, andadipose tissue

• 5n most mammals, glucose is the primarysubstrate or lipogenesis, but inruminants acetate.

• ;e1uires coactors, including ND39, #3,/n2<, biotin - 9(=8 !as a source o(2"

• Acetyl-CoA is the immediate substrate



5mportant notes in lipogenesis

• #he initial - controlling step in atty acidsynthesis is the production o /alonyl8o

• Fatty acid synthase comple) is amultien$yme polypeptide comple) with acylcarrier protein !3" as its part containingse%en en$yme acti%ities

%cetylCo% !alonylCo%

/n0biotinCOO /n0biotin

%"P 1 Pi %$P 1 2CO3

/n0 4 acetyl

Co% carbo+ylase



• 'icarbonate as a source o (2 is

re1uired in the initial reaction orcarbo)ylation o acetyl8o tomalonyl8o in the presence o

#3 - cetyl8o carbo)ylase thatre1uires %itamin 'iotin.





5mportant notes in lipogenesis!cont."

• #he main source o ND39 orlipogenesis is the 3entose 3hosphate3athway !333"

• cetyl8o is the principal buildingblock o atty acids

• longation o atty acid chains occurs inthe endoplasmic reticulum

• hain elongation also occurs inmitochondria but less acti%e and usesacetyl8o as acetyl donor !its unction

is speculati%e"




• Nutritional state regulates lipogenesis

the rate is higher in the well8ed animalwhose diet contains a high proportion ocarbohydrate !Nutritional state o

organism is the main actor regulating therate o lipogenesis"

• #here is in%erse relationship betweenhepatic lipogenesis - concentration oserum FF >? decreased lipogenesis inincreased serum FF !which is associatedwith restricted caloric intake, on a high8

at diet or insulin de@ciency as in D/"

5 t t t i li i




• 9igh at in the diet causes depression olipogenesis, or when there is more thanA0B o at in the diet, there is littlecon%ersion o dietary carbohydrate toat

• 5nsulin stimulate lipogenesis by se%eralmechanism increases glucose transp.

into the cell !e.g. in adipose tissue"• 5nsulin inhibits lipolysis !lipid

degradation" in adipose tissue

• Fatty acid synthase comple) - acetyl8



&hort term - long termmechanisms regulate lipogenesis

• &hort term by allosteric - co%alentmodi@cation o en$ymes

• 4ong term by changes in genee)pression go%erning rates oen$ymes synthesis !F &ynthaseomple) - cetyl8o arbo)ylase

are adapti%e en$ymes"



Oxidation of Fatty Acids:(& Ketogenesis)

• Oxidized to Acetyl-CoA and synthesized from

Acetyl-CoA• Starting material of one process is identical to

the product of the other and the chemical

stages involved are comparable, the fatty acid(FA oxidation is not the simple reverse of FAbiosynthesis! "t is entirely different processta#ing place in a separate cell compartment $%

oxidation in mitochondria, synthesis in cytosol!

Fatty acid.



O+idation of Fatty Acid"$#eto&ene"i"

• 5ncreased in star%ation - D/ leading toketone body production by the li%er!ketosis" when produced in e)cess o%erlong periods, as in D/, cause ketoacidosis!ultimately atal"

• Gluconeogenesis is dependent upon atty

acid !F" o)idation

any impairment in thisF o)idation leads to hypoglycemia. #hisoccurs in %arious states o carnitinede@ciency or de@ciency o essential

en$ymes in F o)idation

'iomedical importance*



O+idation of fatty acid"

• (ccurs in mitochondria

• (rigin o F * blood - cells,transported in blood as Cree attyacids !FF > unesteri@ed state"

• 5n plasma FF o longer chain F arecombined with albumin and in the cell

they are attached to a F bindingprotein !protein E".



• &horter8chain F are more watersoluble and e)ist as the un8ioni$edacid or as a F anion

• F are acti%ated beore beingcataboli$ed in the presence o #3 -o, acyl8o synthetase !thiokinase"

cataly$es the con%ersion o FF toCacti%e atty acid or acyl8o*

F < #3 < o

cyl8o < 33i <

O+idation of fatty acid" )cont.*







• 4ong chain F penetrate the inner

mitochondrial membrane as carnitinederi%ati%es

• cti%ation o lower F - their o)idationwithin mitochondria may occurindependently o carnitine

Acetyl-CoA& carnitine

Acetylcarnitine& CoA.

Carnitine acetyltransferase



'ong-chain FA (Acyl-CoA cannot pass

through the innermitochondrialmembrane, but itsmetabolic product,

acylcarnitine, can

ole of carnitine in the transport of long-chain FA through the inner mitochondrial membrane



Transport of fatty acids from the cytoplasm to the inner mitochondrial space for oxidation. ollowing

activation to a fatty!"oA# the "oA is exchanged for carnitine by carnitine!palmitoyltransferase $. The

fatty!carnitine is then transported to the inside of the mitochondrion where a reversal exchange ta%es

place through the action of carnitine!palmitoyltransferase $$. &nce inside the mitochondrion the fatty!

"oA is a substrate for the b!oxidation machinery.



Ty'e" of FA o+idation

• la ()idation * the remo%al o onecarbon at a time rom the carbo)yl endo themolecule !ha%e been detected in

brain tissue >? it does not re1uire ointermediate and does not generatehigh energy83

• 'eta ()idation * two carbon atoms are

clea%ed at a time rom acyl8omolecules, starting at the carbo)yl endto produce acetyl8o >? produce alarge 1uantity o #3. 5t is the main Fo)idation



Ty'e" of FA o+idation )cont.*

• (mega ()idation * normally a %ery minorpathway and is brought about by hydro)ylaseen$ymes in%ol%ing cytochrome 30 inendoplasmic reticulum H 9= group iscon%erted to a 92(9 group thatsubse1uently is o)idi$ed to 8((9 thusorming dicarbo)ylic acid. #his is usually β8

o)idi$ed to adipic !I" and suberic !" acidswhich are e)creted in the urine

• ()idation o unsaturated F occurs by amodi@ed β8o)idation pathway











108

16

24

146

146 x 51.6* = 7533.6 kJ



,om'ari"on of FA o+idation - FAbio"ynt(e"i" )li'o&ene"i"*

• O+idation$

K locationmitochondria

K uses ND< - FDas coen$ymes

K generates #3

K in%ol%ing acyl8o

deri%ati%es

• Li'o&ene"i"$

K location cytosol

K uses ND3< ascoen$ymes -re1uires #3 <bicarbonate ion

K in%ol%ing acylderi%ati%es boundto the multien$ymecomple)



#eto&ene"i"

• Letogenesis is the generation oketone bodies !acetoacetate, D!8"8=8hydro)ybutyrate > β8(98butyrate -

acetone"

• (ccurs when there is a high rate o Fo)idation in the li%er

• #he en$yme system is inmitoc(ondria, with FF precursor inthe li%er









Letogenesis !cont."

• #wo molecules o acetyl8ocondence to orm acetoacetyl8o,and with the addition o another

acetyl8o produce =8(98=8methyl8glutaryl8o !9/G8o" cataly$ed by9/G8o synthase

• 9/G8o is an intermediate in thepathway o ketogenesis 8? in thepresence o 9/G8o lyase is split

into acetyl8o and acetoacetate







Letogenesis !cont."

• Acetoacetate is in e1uilibrium withD)*/O0butyrate !predominantketon body present in the blood andurine in ketosis" cataly$ed by D!8"8=8(9butyrate D9 - ND9, or spontaneouslycon%erted into acetone releasing (2

• 4i%er is the only organ in non8ruminantsto add signi@cant 1uantities o ketonebodies to the blood







Letogenesis !cont."

• Letone bodies ser%e as a uel ore)trahepatic tissues whileacetoacetate - D!8"8=8(9 butyrate arereadily o)idi$ed by e)trahepatic tissues,acetone is dicult to o)idi$e in %i%o and%olatili$ed in the lungs

• 3rolonged ketosis leads to ketoacidosis

!such as in D/". 5n star%ation

simpleketosis

• /easurement o ketonemia is preerredthan that o ketonuria



li i l t i i d



linical aspects o impairedo)idation o F

• arnitine de@ciency

• arnitine palmitoyltranserase85 de@ciency

• arnitine palmitoyltranserase855 de@ciency

• cute atty li%er o pregnancy• 9/G8o lyase de@ciency

• Jamaican %omiting sickness

• Dicarbo)ylic aciduria• ;esumMs disease

• EellwegerMs !cerebrohepatorenal" syndrome



Metabolism of Unsaturated FA

• ompared with plants, animal tissuesha%e limited ability in desaturating F need 3+F !polyunsaturated F" rom aplant source which are e""ential FA to

gi%e rise to eicosanoic !20" F, romwhich are deri%ed amilies o compoundsknown as eicosanoids.

• icosanoids are physiologicaly -pharmacologically acti%e compoundsknown as prostaglandins !3G",trombo)anes !#", leukotrienes !4#" -

lipo)ins !4"

Metaboli"m of n"aturated FA



Metaboli"m of n"aturated FA)cont.*

• &ome 3+F cannot be synthesi$ed bymammals and are thereore nutritionallyessential

• (ther 20, 22 - 2 polyenoic F maybe detected in the tissues may bederi%ed rom oleic, linoleic, - α8linoleic

acids by chain elongation. #he doublebond present in naturally occuringunsaturated F o mammals are the cis

con@guration

M t b li f t t d FA ) t *



Metaboli"m of n"aturated FA )cont.*

• Trans8+F may compete with cis8+F

• +p to AB o tissue +F ha%e beenound to be in trans con@guration metaboli$ed more like saturated than like

cis8+Ftend to raise 4D4 le%els - lower 9D4 le%els

and thus contraindicated with respect tothe pre%ention o atherosclerosis -

coronary heart disease do not possess essent. F acti%ity and

may antagoni$e the metabolism o essent.F - e)acerbate essent. F de@ciency




• /onounsaturated F are synthesi$ed by

a ∆O desaturase system and synthesiso 3+F in%ol%es desaturase andelongase en$yme systems

• icosanoids are ormed rom 20 3+F!arachidonate and some other 20 F"

• De@ciency o essential 3+F !linoleic,

linolenic - arachidonic acid" leads to ade@ciency syndrome in e)periment ratsinclude scaly skin, necrosis o the tail,

and lesion in the urinary system




• ssential 3+F unctions are %arious,apart rom prostaglandin - leukotriene

ormation. #hey are ound in thestructural lipids o the cell - areconcerned with the structural integrity

o the mitochondrial membrane

M b li f d FA



Metaboli"m of n"aturated FA)cont.*

)ample * arac(idonic acid is presentin membrane, accounts or 8AB o Fin phospholipidsP doco"a(e+anoic

acid !D9 ω=,2*I" synthesi$ed rom α8linolenic acid or obtained directly rom@sh oils is present in high

concentrations in retina, cerebralcorte), testis - sperm. D9 isparticularly needed or de%elopment othe brain - retina and is supplied %ia

the lacenta - milk



'athway from linoleic acid to arachidonic acid. (umbers in parentheses refer

to the fatty acid length and the number and positions of unsaturations.



Bio"ynt(etic 'at(1ay" of Eico"anoid"

• #wo pathways rom arachidonate*

K ycloo)ygenase pathway orms

3rostanoids !3G2 - #2 series * 3GD2,3G2, 3GF2, 3G52, #2"

K 4ypo)ygenase pathway orms

4eucotrienes !4#, 4#', 4#, 4#D,4#" - 4ipo)ins !4, 4', 4,4D, 4"



PGE2

TXA2

LTA4

The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs)

and leukotrienes (LTs) The PGs and TXs are !olle!ti"el# identi$ied as

prostanoids



Bio"ynt(etic 'at(1ay" of Eico"anoid")cont.*

• 3rostanoids are potent biologically acti%esubstances*

K thrombo)anes are synthesi$ed inplatelets and upon release cause%asoconstriction - platelet aggregation

K prostacyclins !3G52" are produced byblood %essel walls and are potentinhibitors o platelet aggregation



Bio"ynt(etic 'at(1ay" of Eico"anoid")cont.*

K 4eucotrienes - lipo)ins are potentregulators o many disease processes a mi)ture o leucotrienes , D - is a slow reacting reactingsubstance o anaphyla)is !&;8" which

is A008A000 times more potent thanhistamine or prostaglandins as aconstrictor o the bronchial airway

musculature



)ynthesis of the clinically relevant prostaglandins and thromboxanes from arachidonic acid.

(umerous stimuli *e.g. epinephrine# thrombin and brady%inin+ activate phospholipase A,

which hydrolyzes arachidonic acid from membrane phospholipids. The prostaglandins are

identified as '- and the thromboxanes as T. 'rostaglandin '-$, is also %nown as

prosta!#!lin The subs!ript 2 in ea!h mole!ule re$ers to the number o$ %&'&% present



)ynthesis of the clinically relevant leu%otrienes from arachidonic acid. (umerous stimuli *e.g. epinephrine#

thrombin and brady%inin+ activate phospholipase A, which hydrolyzes arachidonic acid from membrane

phospholipids. The leu%otrienes are identified as LT. The leu%otrienes# LT"/# LT0/# LT1/ and LT/ are

%nown as the peptidoleukotrienes be!ause o$ the presen!e o$ amino a!ids The peptidoleukotrienes,

LT&4, LT4 and LTE4 are !omponents o$ slo%rea!ting substan!e o$ anaph#laxis The subs!ript 4 in

ea!h mole!ule re$ers to the number o$ %&'&% present

Bio"ynt(etic 'at(1ay" of



Bio"ynt(etic 'at(1ay" ofEico"anoid" )cont.*

together with 4# ' also cause

%ascular permeability, attraction -acti%ation o leukocytes seemsto be important regulators in manydiseases in%ol%ing inQammatory or

immediate hypersensiti%ityreactions, such as asthma

9arious stuimuli e #



Membrane phospholipid

Arachidonate

eu!otrienesipoxins

"rostaglandins#hromboxanes

P2O5P2OLP%5/

%6

LPO78G/N%5/ C8CLOO78G/N%5/

9arious stuimuli, e.#.

%n#iotensin ,

bradyinin.,

/pinephrine

thrombin









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