--f sLa f-t t{. H \I ! L".) L) _> t Lut

\lJ

N.B. Thef inciude small amounts of other steroids and fat-soluble vitamins.

PLASMA L{TSPROTE{NS

Al1 lipids in plasma are transported in thePeripheral apolipoprotein

$Ir",*{}8 y',EPtr&SPlasraa lipids are usually measured afler 12 hours flasting. The total plasma iipidsranges frora 400 - 700 mg/di (mean value 500 mg/dl). The main tirpes of plas,ralipids include the fbllow.ing:

form of lipoproteins. Plasma lipoproteins havethe central core is forrned of non-polar lipids(triacylglycerols and esterified cholesterol).The outer iayer contains the more polar ' Phospholiprds

Clrolesterylsters

lipids (pirospholipids and non-esterifiedcl"rolesterol), and proteins (apolipoproteins). cholesterol

ntegral apol ipoprotein

Apolipoproteins are either peripheral (can be transfelred) or integral (cannot betransfemed). They act as activator for enzymes (e.g, apo c iI activatoi for iipoprotei*Iipase) and are important for receptor_mediated -uptake

of piasma lipoproteins bycertain tissues (e.g. receptors for apo E in liver ..I1, fo, uptake of chyiomicro,s).Plasma lipoproteins are separated into different fractions by two methocis,electrophoresis and ultracentrifugation.

Comparison BetweenUltracentrifugation I'ractions Electrophoresis Fractions

<---_chylomicrons 1 .-3' Non-mobilefraction

+-- VLDL \ _._r!,-Lipoproteins

><./<- LDL '-t \ preo -Lipoproreins

<-- HDL <--_---_> a-Lipoproteins

of linidq l\foo- ',-1"^lYrv4lMlUU

Cholesterol na - 240709'o choiesteryi esters3 0o%non=esterifi ed cholesterol

150-2s0f ree laffy acrds (FFA

,/ <- FFA - Albun-rin complex

CVS Module - Blood Lipitls

I - Electrophoresis

They are separated according to their mobiiity in erectric field.2- Ultracentrifu gation

They are separated according to their density. The higher the protein content thehrgl"l the densify of the particles. The main rractions sepirated inciude:- Chl,lomicrons --*---vrru rvYG

- Y"ry low density lipoproteins (VLDL)

- Intermediate densitv iipoproteins (IDL)- Low densiry lipoproteins (LDLt- I,gl, densiry iipoproteins (FIDL.;- Free fatty acids - aibumin .o*pi"o.

composition of Different Fraetions of Lipoproteins

E4E TAr*Or,{SM f,}F r,fP{}tr}R. {}T,E gNSI- Metabolism of Chylomicrons

I I \B4VI Inrestinat i ^6+==A

i ces /- ffiffiB,,/.\/^ \

.nillliiJ'",,

F*7t--#,-ffirrw,

/ ^\/ ^\Mature

Chylonricrons

i

,,fr'roo'o'cin iipasc

'/ I GlvcerolEt'ApoC&A

I +FFA

HDL

Receptors for Apo E

Apo C&E

/

t

\f/l

TAGI

CE

I

Type ofLipoprotein Density

Protein content % of Iipids Contento//o Types ofA nnntnfei, l Atr. YL,

C&CE ]\iEFA

Chvlnm < 0.95 a tt/L /fr BB B 4VLI]I, 0.95 - 1.006 l0 ,'/n B-100 c&tr 59 2A 20rDL 1.006- 1.019 11 o/,J29 25 45LDI 1.019 - 1.063 20 "/o B-100 14 25 60 I1.063 - 1.210 45 a/o A,C.E&D 45 35 5rr,A - All') > i.281 gg ah Alburnin

fiAo/"

Chyionricron remnants

,

The metabolism of chylomicrons is summa rized, as follows: -

I- svnthesis of nascent chylomicrons hy intestinal cerlsChylomicrons oan'y the absorbeci riierary iipids to iiver and other tissues.They are formed by the following steps: -

a-Synthesis olthe iipid cornponents on ihe smooth enriopiasmic reticuium (SER).b-Synthesis of apolipoproteins by the ribosornes on the rough endoplasmic reticulum(RrR) ApoB-48 forms 18a/o of the apoB-100. The latter represents 100o% expressionof apoB gene, while Apo B-48 rep'esents 4|o/o expression oiapoB gene.c-Assembiy of both lipids and proteins occurs during' transport fiom ER to Goigiapparatus, where they are packaged in secretory vesicles and released to interceilularspace by exocytosis.d-Nascent chylomicrons are drained by the intestinal lacteals to the thoracic duct thento blood stl'eam.

2- conversion of nascent chyromicrons to mature chylornicronsThis occurs by ,eceiving apo C (inciuding apo c II) ani apo E from F{DL

3- Degradation by plasma lipoprotein Iipase enzvmeThis enzyme is attacired to a proteogrycin termei heparansulfatq o, the endotheriarlining of the capillary walls of many tissues e.e. adipose tissues, eardiac and skeletalmuscies, neonatal liver and lactating mammary glandi. Insulin enhances the synthesisof the lipoprotein iipase enzyme and hepari, in.."ur"s its activity itp;p;;,ein lipaseis tenned the clearing factor as it produces ciearance of the turbidit5, produced byciryiomicrons in piasma.Lipoprotein lipase is activated by apo C-II present in chylomicrons and \tDL. Theenzyme catalyzes hydroiysis of triacyiglycerols present ir-r both tipoprotlins intoglycerol and fiee fatt,v acids. Glycerol

_is taken by tirer celrs mainr),, due to higir

activi8- of glycer:ol kinase. Free fatty acids eithe. "rri.,

within the tissuei or transportedbound to plasma albumin for r-rptake and metabolis,r by liver ceils.

4- tr'ormation of chylomicron remnantsAfter hydrolysis of TAG by the iipoprotein lipase, apo C&A are transfer.red to HDI_.The remaining particles are tetmed ch1,l6mig1on remnants. They have less percent ofJAG and higher percent of cholesterol, cholesteryzl este6 urd phospholipids. AlsoTAG is transferred to HDL in exchange with choiestei:yl .st"rr, ir,,i, ;;^;;i;ivzed brnhn!^n+^.-,! ^^L^-- L--^,- -C

r - jcholesteryl ester transfer protein (cETp or termed up* i;;.They are endocltosed by liver cells through specific r,eceptors fbr apo E. In iivercells, the different components are hydroll,ied and metaboliied o...ur"l for synthesisof lipoproteins.

CL/S Motlule - Blood Lipids

II- Metabolism of VLDL, IDL and LDLVLDL are formed mainiy by liver cells and their function in transporl of TAG andcholesterol from iiver to extrahepatic tissues.The metatrolism of VLDL is summarized as follows: -1- Synthesis of nascent VLDL by iiver cellst{ascent VLDL are formed by liver ceils and contain a specific protein termed apo B-I (Lr.

2- Conversion to mature YLDLNascent VLDL are released from iiver celis into blood, where tirey receive apo C andapo E from I{DL to form the mature VLDL.3- Degradation by plasma lipoprotein lipase enzymeAs in cirylomicrons, this enzyme catalyzes hydrolysis of the TAG into glycerol andfree fatry acids.4- Formation of VLDL remnants (IDL)They are aiso termed intermediate density lipoproteins (IDL). They are formed afterthe action of lipoprotein lipase arrd removal of apo C that returns back to HDL.5- Conversion of IDL to LDLThis is achieved by further hydrolysis of TAG, and removal of apo E (its return backto HDL). Aiso TAG is transfened to HDL in exchange with cholesteryl esters, this iscatalyzed by cholesteryl ester transfer protein (apo D).6- Fate of LDLLDL bind to specific apo B-100 receptors, in both extrahepatic tissues QA%) andliver (70o/o) where they are endocytosed and tireir contents are rnetaboiized. LDL areimporlant source of cholesterol to extrahepatic tissues. High levels of LDL -cholesterol increase the risk of atherosclerosis.

\B:1007\/l+srrfl

- ,_{_u-Y_$-r $LY_Y-U-Y.gJ.SI,_Y_Yr_g-g-E IYJJJSgYY_g_$-U-g g_rq-Y-Jt/

NascentVLDL

\B- r07--i+.-,r#"-I Eggug \l^l-V-Y-YIl r It-u*$_rl L I

I tj_g_*_s_\ /, Y-*-$ 9-U\ /-({.!{5vrv

_-,=-->

Apo E Mutu."VLDL

Receptors fbr Apo B-100

Clycerol+ FFA

(C&i

Receptors for Apo B- l 00

Atherosclerosis: It is the deposition of-lipids, especiaily cholesterol and cholesterylesters in arterial wali. Expost-u'e of LDL to oxidant produces oxidized or modifiedLDL' Excessive uptake of LDL (due to high prasma reversl or modified LDL bymacrophages causes the transformation of these celis into foam cells. Accumulatedfoam cells in arterial walis stimulate release of giowth fuctors and proiiferation ofsmooth muscles and formation of plaque (atheroma). These produce nanowing ofbiood vessels and predispose to thrombosis. Antioxidants iike vitainin C anii Edecrease the incidence of atherosclerosis.III- Metabolism of HDLi hey are fbrmed by iiver cells and sraall intestine as discoidal HDL which are mainlyformed of phospholipid biia)rer, fiee choiesterol a,d apoiipoproteins (A, c, E & D).then accept free choiesterol Irom extrahepatic tissues, where it is esterified by LCAT.LCAT is activated by apo A present rn HDL and catalyzes transfer of acyl group tiomposition 2 of lecithin to cholesterol to form cholesteryl esters u,ri tfroi.cithin.Choiesteryl esters form a central hvdrophobic core that pushes the phospirolipidbilayer apaft and convefis tire discoiclri fftf into the sphericat I{Df ,.- IIDL act as reservoir for different apoproteins (C^&E), which are important lormetaboiism of chylomicrons and VLDL.- HDL by the mean of GETP (apo D) provide choiesteryl esters to chylomicronremnants and LDL in exchange with triacylglycerols.

: rDl are endocytosed by iiver cells, where cholesteryl esters are hydrolyzed. Thefree cholesterol relea-sed is either repacked into iipoproteins. converted to bile acids orsecreted in bile. So, F{DL are important for r.**r1 of cholesterol form th" ti;;; ;;ll: 1*-":

(reverse cholesterol transport) and high levels of FIDL protecr asainstatnerosc lerosrs.

Phosphoiipidbilayer Discoidal IIDL

l--,/

/'ha

Cholesterol

Extrahepatictissues

Phosphol ipid outer iaverCholesteryl esters(hydrophobic core)

Spherical HDL

IV- Metatrolism of Plasma Free Fatty AcidsFree fatt5' acids (FFA) or non-esterified fatty acicls (NEFA) are transpofiedconjugated to plasma albumin. They are produced Ll,iipolysis in adipos",irr;;;;;;;the action of lipoplotein lipase on chylomicrons o. tirnL. Their levels increase in allcases of enhanced lipol1'sis e.g. fa.sting and diabetes meliitus. Thev are metaboiized indifferent tissues for production of energ)r especially during fasiing. In liver celis,during starvatio* or in case ol uncontroiied diabetes mellitus, fiee fatty acids arepaitially oxidized and produce ketore bodies. ' - -----r

CVS Module - Bl6od Lipids

Disorders of Plasma Lipoproteins @yslipoproteinemias)A- t{yperlipoproteinemia1. Primary hyperlipoproteinemiaType I or deficiency of plasma lipoprotein lipase: This produces increase in theplasma levels of chylomicrons and VLDL.Type II or f,'amilial Hypercholesterolemia: Due to defect in LDL receptors in iiverand other tissues, which produces marked increase in LDL.Type III or tr'amilial Hyperlipoproteinemia: There is increase in chylomicronsand VLDL remnants due to deficiency of remnants clearance by liver cells.Type IV or f,'amilial Hypertriacylglycerolemia: Due to overproduction of VLDLwhich is usually associated with coronary heart diseases, type II diabetes mellitus,obesity and aicoholism.

2. Secondary HyperlipoproteinemiaSecondary hyperlipoproteinemia is due to other diseases1- Diabetes mellitus3- Hypothyroidism5- Obesity

2- Obstructive jaundiee4- Nephrotic syndrome

B- Hypolipoproteinemia1 -Ab etalipoprotein emia

Failure of synthesis of apo-p, defective forrnation of chyiomicrons, VLDL and LDL.2-Deficiency of LCATMarked decrease in cholesterol esters and HDL (the main site of esterification ofcholesterol).

-l

,rt -rr"rt - rrr:"r,

METABOLISM OF CE{SI,ESTEROLDietary Sources

Brain, liver, kidney, red rneat and egg yolk are rich sources for cholesterol.

E{OSYNTHESIS OF CFIOLESTER*E,

All nucleated cells are capable of forming their cholesterol. Plasma cholesterol isformed mainly by liver cells. The enzymes responsible for synthesis of cholesterol arepresent in the microsomal and cytosolic fraction of cells. The biosynthesis ofcholesterol includes the following steps:

2 cwr-co-s-coAAcetyl-CoA

co2, H2o

lsoplenoid unit (C5) 'U ,

CH3-CO-CHz-CO^-S-CoAAcetoacetyl-CoA

(HMc-CoA)

0xidocyclaseSqualine (C30)

--> Lanostrol (C30)

Ketothiolase

--\*coA-sH

I anr-co-s-coAHMG-CoAsynthase | _.,-'e""tyl_CoAHuo {

-.-*r J ----^ coA-sH

{ OHI HMG-CoA reductase OH.--r .l_-, Irg99:.r,-ti",rrcH2oH Hooc-.n,-+- cHz-co-s-coA

CHI CH'. ?NADP. 2NADPH,]"Mevalonate l",it, ' 3-Hydroxy-3-methylglutaryl-CoA

3 CHr

Reductase Isomerase

Cholestrol (C27) *--\- Desrnostrol (C27) <-- Zymostrol (C27)

L

Regulation of Cholesterol SynthesisHMb - CoA reductase is the key enzyme for cholesterol synthesis. It is present in two

forms active (dephosphorylated) and inactive (phosphorSzlated)' The activity of the

enzyme is regulated by cAMP dependent enryme system. increased by carbohydrate

feeiing and by insuiin and decreased 'oy fasting and by glucagon. HMG - CoA

reductase is inhibited (feedback inhibition) by mevaionate and choiesterol'

Functions of Cholesterol1- Formation of iipoproteins: Cholesterol and

formation of plasrna and cell membrane lipoproteins'

2- Synthesis of steroid hormones: Cholesterol

estrogens, progesterone, and corticoids'

3- Synthesis of Vitamin D3

4- Synthesis of bile acids and salts: Biie acids

cholesterol.

choiesteryl esters enter in the

is the precursor of androgens,

are formed in the iiver fi'om

ExcretionAbout 1g of cholesterol is excreted daily, 5Ao/o tti the form of bile acids and 50o/o as

chol esterol.

Plasma CholesterolTlre total piasma cholesterol ranges form 120 - 240 mgldL with mean value about 180

nrg/dl (recommended level < 200 mgidl-), TAok are in the form of esters with fatty

acids. plasma cholesterol is provided mainly by the liver and intestine. Esterification

of choiesterol occurs mainly in piasma iipoproteins by the action of plasma LCAT.

75r/o af plasma cholesteroi is transported in LDLs. Elevated LDL&{DL eholesterol

ratio more than 411( atherogenic index) pledisposes to atherosclerosis and coronaty

hearl disease. LDLs act as carriers of cirolesteroi for extrahepatic tissues. HDLs act as

the main carrier of cholesterol from tissues to the liver (reverse cholesterol

transport), where cholesterol is excreted into biie, convefied to biie acids or reused in

synthesis of liPoProteins.

Factors that Increase Plasrna ChtllesterolHypercholesterolemia means ievels above 240 mgldL'

ft "

fottowing factor:s predispose to hypercholesterolemia.

1- Diet rich in carbohydrates, saturated fatty acids and cholesterol.

2- Hypothyroidism as thyloxine stimulates conversion of choiesterol to bile acids.

f- piaUetes Mellitus due to increased synthesis and decreased clearance of plasma

lipoproteins..+- Obesity (usually associated with hyperlipoproteinemia)'

5- Obstructive jaundice due to decreased excretion of cholesterol and bile acids.

6- Nephrosis (untnown mechanism).

7- Coffee drinking and cigarette smoi<ing increase mobilization of FFA from adipose

lissues and increase plastna lipoproteirls'g- Familial hypercholestero1emia (type 1I hyperlipoproteinemia).

CVS Module - Blooel Lipitls

Factors that Decrease Plasma CholesterolHypocholesterolemia occurs when plasma cholesterol level drops below 120 mgidl,This drop may be due to one or more of the following causes;1- Prolonged fasting or starvation decrease the activify of HMG -CoA reductase.2- Diet rich in USFA (oils) and poor in SFA, cholesterol and carbohydrates.3- Liver diseases.4- Hyperthyroidism( thyroxine stimulates conversion of cholesterol to bile acids).5- Chronic infections e.g. tuberculosis,

li