Metabolism of Lipid 2010

7/23/2019 Metabolism of Lipid 2010

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METAB

OLISM

LIPID

2011

Dr. LOO HIAN DAO


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INTRODUCTION of LIPIDS

common property of lipid: relatively insoluble in water and

soluble in nonpolar solvents such as ether and chloroform.

high energy value

fat-soluble vitamins (A,D,E,K)

thermal insulator in the subcutaneous tissues and around cerorgans.

electrical insulators, allowing rapid propagation of depo

waves along myelinated nerves.

transporting lipids (lipid + proteinlipoprotein


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CLASSIFIED Simple lipids: Esters of fatty aids !it" #ario$s alo"ols%

a. Fats: Esters of fatty aids !it" &lyerol% Oils are fats i' t"e li($id

b. )a*es: Esters of fatty aids !it" "i&"er mole$lar !ei&"t mo'o"

Comple* lipids: Esters of fatty aids o'tai'i'& &ro$ps i' adalo"ol a'd a fatty aid% a. P"osp"olipids: Lipids o'tai'i'&+ i' additio' to fatty aids a'd a'

p"osp"ori aid resid$e% T"ey frequently have nitrogen containing basessubstituents! eg! in &lyerop"osp"olipids t"e alo"ol is glycerol an insp"i'&op"osp"olipids t"e alo"ol is sp"i'&osi'e%

b. ,lyolipids -&lyosp"i'&olipids.: Lipids o'tai'i'& a fatty aid+ sp

ar/o"ydrate% c. Ot"er omple* lipids: Lipids s$" as s$lfolipids a'd ami'olipids% L

may also /e plaed i' t"is category.

Pre$rsor a'd deri#ed lipids: T"ese i'l$de fatty aids+ &lysteroids+ ot"er alo"ols+ fatty alde"ydes+ "etone boies! hyrosoluble vita%ins! an hor%ones.


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estio' a'd a/sor tio' of tria l l erols


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LIPO&'N'SIS


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Elongation of Fatty Acid Chai

his path!ay (the "microsomal s

elongates saturated and unsaturated fatt

$oAs (from $%& up!ard) by t!o carbon

malonyl-$oA as acetyl donor and 'ADreductant, and is cataly*ed by the mic

fatty acid elongase system of enzymes


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REG U LATES LIPO G EN Li#ogenesis converts sur#lus glucose an inter%eia

#yruvate! lactate! an acetyl$Co( to fat! assisting th#hase of this feeing cycle.

Li#ogenesis is e#resse uner conitions of restricinta"e! on a fat iet! or )hen there is a e*ciency of iniabetes %ellitus.

These latter conitions are associate )ith

concentrations of #las%a free fatty acis! an relationshi# has been e%onstrate bet)een he#atic an the concentration of seru%$free fatty acis.

Li#ogenesis is increase )hen succrose is fe insteabecause fructose by#asses the #hos#hofructo"ina#oint in glycolysis an +oos the li#ogenic #ath)ay.


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Regulation of Lipogenesis

(cetyl$Co( carbo,ylase is an allosteric en-y%e an is a

itrate+ !"i" i'reases i' o'e'tratio' i' the )an is an inicator of a #lentiful su##ly of acetyl$Co(! anacyl$Co( inhibits its activity.

(cyl$Co( %ay also inhibit the %itochonrial tritra'sporter+ t"$s pre#e'ti'& ati#atio' of t"e egress of citrate fro% the %itochonria into the cytosol.

(cyl$Co( causes an inhibition of #yruvate ehyroinhibiting the (TP$(DP e,change trans#orter of %itochonrial %e%brane! )hich leas to intra%itochonrial (TP/0(DP/ ratios an therefore to cactive to inactive #yruvate ehyrogenase.

Insulin activates acetyl$Co( carbo,ylase )hereas gl

e#ine#hrine have o##osite actions.


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Fatty acids with an odd number


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Fatty acids with an odd number

are oxidized by the pathway

producing acetyl-o!, until

(propionyl-o!" residue remain

#his compound is converted to

constituent of the citric acid cyc $ence, the propionyl residue fr

fatty acid is the only part of a

glucogenic.

%eroxisomes &xidize 'ery o

!cids and leads to the formati

and $)&) (from the fla

dehydrogenase step", which is

catalase.

#hese enzymes are induced by

in some species by hypolipidem

clofibrate.


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1'TO&'N'SIS


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I i d O id i fF A id Gi Ri


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I pai!ed O "idation of Fatty Acids Gi#es Rise toO ften

Associated % ith & ypoglyce ia

Ca!nitine deficiency in the new born and especially in preterm infants

2y#oglyce%ia! i%#aire fatty aci o,iation an laccu%ulation

%uscular )ea"ness

Treat%ent is by oral su##le%entation )ith c CPTI deie'y: only the liver

CPTII deie'y a3ets primarily s4eletm$sle a'd+ !"e' se#ere+ t"e li#er

I i d O id ti fF tt A id Gi Ri t


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I pai!ed O "idation of Fatty Acids Gi#es Rise toO ften

Associated % ith & ypoglyce ia

'a aican #o iting sic(ness caused by eating the unripe fruit of the a+ee tree

contains the toin hypoglycin.

inactivates %eiu%$ an short$chain a

ehyrogenase! inhibiting $o,iation acausing hy#oglyce%ia.


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1'TO(CIDOSIS igher than normal uantities of +etone bodies p

blood or urine constitute *etonemia (hyper*e

*etonuria, respectively. #he overall condition is c

!cetoacetic and -hydroxybutyric acids are bot

strong acids and are buffered !hen present in bl

tissues.

o!ever, their continual ecretion in uantity

depletes the al+ali reserve, causing *etoacidosis.

fatal in uncontrolled diabetes mellitus.


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METABOLISM OF 56SAT57ATED FATT8 ACID

inoleic and -linolenic aci

as the nutritionally essential

Arachidonic acid can be

linoleic acid.

Double bonds can be

introduced at the /, 0,

positions in most animalsbeyond the 2 position.

3n contrast, plants are able

the nutritionally essential fa

introducing double bonds at

%0 positions.


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METABOLISM OF UNSATURATED FATTY ACID

5everal tissues including

considered to be respo

formation of monounsaturated fatty

saturated fatty acids.

67'78'5A89AED

A9E 5;'E53


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'ICOS(NOIDS


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'ICOS(NOIDS #hromboxanes are synthesized in platelets and upon re

vasoconstriction and platelet aggregation.

heir synthesis is specifically inhibited by lo!-dose aspirin.

%rostacyclins (%)" are produced by blood vessel !alls an

inhibitors of platelet aggregation.

5lo!-reacting substance of anaphylais (/-!" is a miture of leu

D/, and E/. his miture of leu+otrienes is a potent constrictor of tair!ay musculature.

hese leu+otrienes together !ith leu+otriene =/ also cause vascular

and attraction and activation of leu+ocytes and are important regula

diseases involving inflammatory or immediate hypersensitivity react

asthma.


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'ST'RI3IC(TION


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T8PE of P9OSP9OLIPID


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T8PE of P9OSP9OLIPID SP986,OLIPID

Gliserolipid

Fosfolipid Sp

Triasil&liserol E!e lise olipid

Sphinofosfo

pid

Simpa'a'adiposa

Lipoprotei'dara"3osfatiil"olin 4lesitin53osfatiiletanola%in

4sefalin53osfatiilserin

3osfatiil inositol bisfosfat3osfatiilgliserol

1arioli#in

#l$s%$loen#AF Sfino%ielin

,liserofosfolipid


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Phos#holi#is

So%e #hos#holi#is have s#eciali-e functeg! i#al%itoyl lecithin is a %a7or co%#onel$'& s$rfata't+ !"i" is la4i'& i'respiratory distress synro%e of the ne)

Inositol #hos#holi#is in the cell %e%branas #recursors of "ormo'e seo'dmesse'&ers+ a'd plateletati#ati'& fais a' al4ylp"osp"olipid%

Gl hi li id


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Glycosphingolipids

&lycos#hingoli#is! containing s#hingsugar resiues as )ell as fatty aci athe outer lea+et of the #las%a %e%btheir oligosaccharie chains facing oufor% #art of the glycocaly, of the cel

an are i%#ortant 485 in cell ahesion an cell recognition6

495 as rece#tors for bacterial to,ins 4eg! tcauses cholera56 an

4:5 as (;O bloo grou# substances.

LIPID TR(NSPORT


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LIPID TR(NSPORT

3our %a7or grou#s of li#o#roteins have beenienti*e that are i%#ortant #hysiologicallyan in clinical iagnosis. These are 485 "ylomiro's+ deri#ed from i'testi'al

absor#tion of triacylglycerol an other li#is6

495 #ery lo! de'sity lipoprotei's -;LDL+ orpre


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LIPID TR(NSPORT


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(#oli#o#roteins Apolipoprotei's arry o$t se#eral r

-1. t"ey a' form part of t"e str$t$relipoprotei'+ e&+ apo B=

-2. t"ey are e'0yme ofators+ e&+ CII lipoprotei' lipase+ AI for leit"i':"ole

ayltra'sferase+ or e'0yme i'"i/itors+ AII a'd apo CIII for lipoprotei' lipase+for "olesteryl ester tra'sfer protei'=

a'd ->. t"ey at as li&a'ds for i'terat

lipoprotei'


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9?@ years of stuiesA9?@ years of stuiesA


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y

Patients with smaller LDL size have greater

at any given level of LDL-C.

y

Patients with smaller LDL size have greater

at any given level of LDL-C.

LDLCholesterol

Balance

130 mg/dL 130 mg/dL

Large LDL

(Pattern A)

Small LD

(Pattern

Higher riLower risk

But they a

have mo

particle


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FATT8 LI;E7


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FATT8 LI;E7 atty livers fall into t!o main categories.

#he first type is associated !ith raised levels of plasma free fatty

resulting from mobilization of fat from adipose tissue or from theof lipoprotein triacylglycerol by lipoprotein lipase in etrahepatic tis

he production of ?>D> does not +eep pace !ith the increasing inf

esterification of free fatty acids, allo!ing triacylglycerol to accumul

a fatty liver.

his occurs during starvation and the feeding of high-fat diets. #he ability to secrete '0 may also be impaired (eg, in starvati

uncontrolled diabetes mellitus, twin lamb disease, and *etosis in

infiltration is sufficiently severe to cause visible pallor (fatty appear

enlargement of the liver !ith possible liver dysfunction.

FATT8 LI;E7


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FATT8 LI;E7 #he second type of fatty liver is usually due to a met

bloc* in the production of plasma lipoproteins, thutriacylglycerol to accumulate.

heoretically, the lesion may be due to (%) a bloc+ in apolipoprotein synthesis,

(4) a bloc+ in the synthesis of the lipoprotein from lipid and

apolipoprotein,

(B) a failure in provision of phospholipids that are found in

lipoproteins, or

(/) a failure in the secretory mechanism itself.

6 l " li f tt li di


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6o'alo"oli fatty li#er dise

1onalcoholic fatty liver d(1!F0" is the most com

disorder !orld!ide.

Chen accumulation of lipi

becomes chronic, inflamm

fibrotic changes may deve

to nonalcoholic steatohep

(1!$", which can progr

diseases including cirrhos

hepatocarcinoma, and liv

alo"oli fatt li er disea


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alo"oli fatty li#er disea

!lcoholic fatty liver is the first stage in alcoho

disease (!0" which is caused by alcoholism ultimately leads to cirrhosis.

$hanges in the 'ADF'ADG

7idation of ethanol by alcohol dehydrogenase

excess production of'AD.


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he increased 'ADF'ADG ratio also causes

increased lactateFpyruvate, resulting in

hyperlacticacidemia, which decreases excretionacid, aggravating gout.

So%e %etabolis% of ethanol ta"es #lace v


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cytochro%e P=B?$e#enent %icroso%al o,ii-ing syste% 4'OS5 involving N(DP2.

This syste% increases in activity in "ro'alo"olism%

'thanol also inhibits the %etabolis% of sorugs! eg! barbiturates! by co%#eting for

cytochro%e P=B?$e#enent en-y%es.


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Impairme't of Ot"er Meta/


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Proesses

6AD9?6AD@MALATEASPA7TATES95TTLE @

7ESPI7ATO78C9AI6

I69IBITTCA C8C

I69IBITED of,L5CO6EO,E6ESIS

98PO,L8CEMIA

ACE

LIPO,E6ESIS @

FATT8 LI;E7

98PE7LIPIDEMIA

,L8CE7OL >P @

LACTATE?P875;ATE @

LACTIC ACIDOCIS

EC7ETIO6 of57IC ACID

98PE757ICEMIA

ETO,E6E

ETOSIS

FFA @

T7IAC8L,L8CE7OL @

98PE7


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Adipose tissue secretes hormones such as adiponectin, which modulates glucose an

metabolism in muscle and liver, and leptin, which regulates energy homeostasis.

;RON (DIPOS' TISSU'


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=ro!n adipose tissue is the

site of "nonshivering

thermogenesis.# 3t is found in

hibernating and ne!born

animals and is present in small

uantity in humans.

hermogenesis results from

the presence of an uncoupling

protein, thermogenin, in the

inner mitochondrial membrane.

Cholesterol


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Cholesterol Cholesterol is #resent in tissues an in #las%a either a

cholesterol or as a storage for%! co%bine )ith a longfatty aci as cholesteryl ester.

Cholesterol is an a%#hi#athic li#i an as such is an estructural co%#onent of %e%branes an of the outer #las%a li#o#roteins.

It is synthesi-e in %any tissues fro% acetyl$Co( an #recursor of all other sterois in the boy such ascorticosterois! se, hor%ones! bile acis! an vita%in

(s a ty#ical #rouct of ani%al %etabolis%! cholesterofoos of ani%al origin such as egg yol"! %eat! liver! an

cetyl Co $C&

Stage 1 Biosy't"esis" l t


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evalonate

ctive "soprenoi#s $C%&

'(ualene $C)*&

)+PC,

'everal

Con#ensation 'teps

)DP

DPH

DP/

Stage

'(ualene $C)*&

Cyclization

Squaleneepoxidase/cyclase

Lanosterol $C)*&$0-ring structure&

,DPH

DP/

Stage 3Lano

,

DPH

DP/

Cho

cetyl Co $C&

H4-Co

HMG-CoA

Reductaseevalonate $C5&

DPH

DP/

rate-#etermining step

cholesterol is fee#6ack inhi6itor mevalonate is fee#6ack inhi6itor

target site for statin #rugs

"olestero

The ER is !he pri%$r( si!e of )holes!erol s(n!hesis


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2&$Co( reucrate$li%iting en

cholesterol b#ath)


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E(NT2'L(S(


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E(NT2'L(S(

THERAPY of HYPERCHOE!TERO


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Signi*cant reuctions of #las%a cholesterol can be

eFecte %eically by the use of "olestyrami'e or surgically by the ileal e,clusion o#erations.

;oth #roceures bloc" the reabsor#tion of bile acicausing increase bile aci synthesis in the liver.

This increases cholesterol e,cretion an u#$regulatrece#tors! lo)ering #las%a cholesterol.

Sitosterol is a "ypo"olesterolemi agent that bloc"ing the absor#tion of cholesterol fro% thegastrointestinal tract.



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The for%ation of cholesterol

at various stages in thebiosynthetic #ath)ay.

The stati's i'"i/it 9M,CoA red$tase+ t"$s u#$

regulating LDL rece#tors. Statins currently in use

inclue ator#astati'+sim#astati'+ a'dpra#astati'%



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Fi/rates such as lo/rate a'd &em/ro0il at m

lo)er #las%a triacylglycerols by ecreasing the secretriacylglycerol an cholesterol$containing


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p p $ %

Ty#e of LDL boun to (#o; an (#o

Prothro%botic ;ining o%ain si%ilar to #las%inogen

co%#ete! favoring thro%bosis

Proatherogenic #referentially bins o,ii-e #hos#holi

an ta"en u# into athero%atous #laqu


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ipoprotein $a%


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Metabolism of Lipid 2010

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