METABOLISMUL

LIPIDELOR &
LIPOPROTEINELOR

Teme
Lipide plasmatice
Lipoproteine, clasificare
Ci de metabolizare ale Lp
Dislipidemiile Factori de risc
aterogen
Ateroscleroza
Tratament
Tratamentul
ul AS vis sau realitate ?!

Lipidele in organism -rol

Grup heterogen de compui chimici (sunt combinaii

ale acizilor grai (AG) cu alcooli sau amine

Insolubile n ap, solubile n solveni organici apolari

(cloroform, tetraclorur de carbon, benzen)

Rol - energetic (TG, AGL)

- structural (fosfolipidele)
- funcional (acizi biliari ,hh.steroizi, prostaglandine/
leucotriene, etc)

15- 20% din masa corporal a unui adult normal

conformat

Lipidele plasmatice
Colesterol
Trigliceride
Fosfolipide
Acizi grasi liberi

Colesterolul
Steroid
Avem nevoie de el (nu prea mult, insa) pentru:
structura membranelor celulare si
subcelulare, vitamina D, saruri biliare, hormoni
sexuali si adrenocorticali
Este transportat pe Lp plasmatice (LDL)
Trece liber din lumenul vascular in spatiul
subendotelial
Cantitate mare acumulare AS

Acizii gra
grai
Saturati: legaturi simple C-C: Ac. palmitic (16C), Ac.
stearic (18C),
Mononesaturati: 1 legatura dubla C=C
oleic (18C:1), palmitoleic (16C:1)
Polinesaturati: >1 legatura dubla C=C
linoleic (18C:2), arachidonic (20C:4)
Omega-3:
docosahexaenoic (22C:6), eicosapentaenoic (20C:5)

Lipoproteinele

Lipoproteine: Colesterol
Fosfolipide
Colesterol
Trigliceride
Proteine
Protein
e
Densitate: mica vs mare
VLDL: trigliceride
spre tesutul adipos
LDL: Colesterol spre
tesuturi
HDL: Colesterol spre ficat
(gunoier
gunoier)
Col
Colesterol
esterol--ru: VLDL, LDL
Col
Colesterol
esterol--bun: HDL

Apoproteine
ApoP

GM (kD)

Sintez

Funcii

A-I

28

Intestin, Ficat

Protein structural a HDL, chilomicronilor, activator al LCAT

A-II

17.4

Intestin, Ficat

Protein structural a HDL, activator al Lipazei hepatice

A-IV

44.5

Intestin

Efluxul colesterolului i transportul lui la ficat, activator LCAT

B-100

514

Ficat

Protein structural a LDL, IDL, VLDL; ligand pentru receptorul LDL

B-48

241

Intestin

Esenial pentru sinteza i secreia Ch i VLDL

C-I

6.6

Ficat

Activator al LCAT n plasm, este transferat ntre HDL-VLDL

C-II

8.9

Ficat

Activator al LPL; n plasm, este transferat ntre HDL VLDL, chilomicroni

C-III

8.8

Ficat

Reglator al LPL (inhibitor)

24

Ficat

Prezent n structura HDL, particip la transferul CE ntre LP

34

Ficat, Creier, Rinichi

Protein structural a VLDL, Ch, resturile Ch, IDL i HDL; ligand pentru
receptorii resturilor Ch i IDL, n hepatocite

30

Protein structural a HDL

75

Protein structural a VHDL

50

Protein structural a Ch i VLDL, cofactor al LPL

70 90

Ficat, Creier, Ovar,

Testicul

Transportul lipidelor, nnoirea membranelor, moartea celular programat,

reglarea sistemului complement

45

Transportul TG

Colesterolul LDL si HDL

3 straturi:
Intern: Esteri de Colesterol, Trigliceride
Mediu: Fosfolipide si Colesterol
Extern: Apolipoproteine A sau B (transport si interactiuni
membranare)

Antioxidanti
Vitamina E
(tocopherol)
in HDL si LDL
protectie
anti oxidare

Clasificarea dup
dup densitate a Lp

Clasificarea electroforetic a Lp

Enzime i proteine de transfer

importante n metabolismul LP
Enzima/ Locatie
Proteina

Activatori Inhibitori Substrat

LPL

Endoteliul:
t. miocardic,
muscular, adipos,
gl.mamara

Apo C II + Apo C III,

Clheparina

TG Ch,
VLDL

HTGL

Endoteliul:
capilarelor
intrahepatice

Apo A II

TG IDL,
HDL2

LCAT

HDL3

Apo A I, C I
Apo A IV

CL HDL3

ACAT

intracelular

CL

CL i.cel

CETP

VLDL, HDL

Apo D

Receptori lipoproteinici
Receptori
-----------

SR B
SR B1

R LDL

LRP

SR - A

Structura

1x839Aa
5 domenii

1x839Aa
5 domenii

3x450Aa
6 domenii

Ligand

N - term
Apo
B100/E

N -term
Apo E/
B100

C term

C term
Apo AI

LP

LDL

IDL

LP ox,
LP Ac

LP ox
HDLnasc

Tesut

Hepatic, Gl
CSR,
sexuale

Hepatic

MQ
Subendote
alial

t 1/2

1,5 zile

Reglare

Down Reg

Caracterist

CD 36

sapt

Down
Reg

SR-C,
LOX-1

LP ox

Catabolizarea Lipidelor exogene

SR A

Metabolismul intracelular al
colesterolului
Oxysteroli

LXR + RXR - SREBP SCAP Proteaza --> RLDL

Sistemul HDL

ABC A1

CERP

ATP Binding Cassette A1

Col Efflux Regulatory Protein

Pharmacologic Therapy to Promote

Reverse Cholesterol Transport LXR ligands

Feces

Bile

A1
FC

Liver

LCAT

CE
SR-BI

A1

CE
Mature
HDL

FC
Nascent
HDL

CE
FC
Macrophage
(ABC A1)

CE=cholesterol ester ;FC=free cholesterol; SR-BI=scavenger receptor class-B, type I;

A1=apolipoprotein A1; LCAT=lecithin cholesterol acyltransferase; HDL=high-density
lipoprotein

HDL Metabolism
Nascent HDL (lipid(lipid-poor apolipoprotein A1 [Apo A1])
is produced by the liver and intestine
intestine
liver

TGRL

particle
uptake

LPL
selective
uptake
apo A1
CETP
SR-BI
HL, EL

ABC A1
peripheral cells

HDL2
LCAT

HDL3 PLTP
cubilin

kidney

preHDL

Von Eckardstein A et al. Curr Opin Lipidol 2000;11:627637.

surface
remnants

Ateroscleroza - faze
Phase I: Initiation

~ 10 years

Phase II: Progression Phase III: Complication

~ 20 years

~ 30 years

~ 40 years

~ 50 years

Endothelial function
Stary HC et al. Circulation 1995;92:1355-1374.

Factori majori de risc

Cardiovascular
Istoric Familial de BCV
Vrsta brbai > 45, femei >55 ani
Fumat
LDL Colesterol crescut
Hipertensiune > 140 / 90 mmHg
Obezitate
Sedentarism
Diabet zaharat
(Homocysteina)

Reductions in CHD Event Rates

by Total Chol Differential in Statin Trials
Change CHD Events

0.4
0.2

Post-CABG
LIPID
AFCAPS
CARE
WOSCOPS
HPS
LIPS
4S

ALLHAT-LLT

0.0
-0.2
-0.4
-0.6
-0.8
-1.0

Cardiovascular
events

0
5
10
15
20
25
30
% Change in Total Cholesterol (Control Treatment)

Regression line from metameta-analyses of 45 longlong-term trials of statin and other cholesterolcholesterollowering interventions
ALLHAT Collaborative Research Group. JAMA 2002;288:29983007.

Interpretarea valorilor parametrilor metabolismului

lipidic la aduli, n funcie de riscul cardiovascular
Parametrul

Valori patologice

Valori critice*

Indivizi cu risc sczut

> 240 mg/dl (6,21 mM/l)

> 260 mg/dl (6,72 mM/l)

Indivizi cu risc crescut

> 200 mg/dl (5,17 mM/l)

> 240 mg/dl (6,21 mM/l)

Indivizi cu boal AS**

180 mg/dl (4,65 mM/l)

> 200 mg/dl (5,17 mM/l)

Indivizi cu risc sczut

>160 mg/dl (4,14 mM/l)

>190 mg/dl (4,91 mM/l)

Indivizi cu risc crescut

>130 mg/dl (3,36 mM/l)

>160 mg/dl (4,14 mM/l)

Indivizi cu boal AS**

>100 mg/dl (2,59 mM/l)

>130 mg/dl (3,36 mM/l)

Indivizi cu risc sczut

<35 mg/dl (0,91 mM/l)

<30 mg/dl (0,78 mM/l)

Indivizi cu risc crescut

<40 mg/dl (1,03 mM/l)

<35 mg/dl (0,91 mM/l)

Indivizi cu boal AS**

<45 mg/dl (1,16 mM/l)

<40 mg/dl (1,03 mM/l)

Indivizi cu risc sczut

>200 mg/dl (2,29 mM/l)

>500 mg/dl (5,71 mM/l)

Indivizi cu risc crescut

>200 mg/dl (2,29 mM/l)

>200 mg/dl (2,29 mM/l)

Indivizi cu boal AS**

>150 mg/dl (1,71 mM/l)

>200 mg/dl (2,29 mM/l)

Colesterol total

LDL-Colesterol

HDL-Colesterol

Trigliceride

Clasificarea fenotipic a dislipidemiilor

tip

Denumirea:

Ser:

Lp:

TG

Col

Simptome

Hiperchilomicronemie

+++

Ch

+++

+/N

steatoz, lipaemia
retinalis,
pancreatit

IIa

Hipercolesterolemie
izolat

Clar

LDL

+++

xantelasme,
gerontoxon

IIb

Hipercolesterolemie cu
hipertrigliceridemie

+ / clar

LDL, VLDL

++

++

xantelasme,
inflamaie
microvascular

III

Boala benzii beta largi

IDL

+++

+++

xantomatoz
eruptiv

IV

Hiper-prelipoproteinemie

++

VLDL

+++

Forma mixt ereditar

+++

Ch, VLDL,
LDL

+++

+++

Clar/+

hepatomegalie,
xantoame
adipozitate,
xantoame

Diagrama EAS

Endoteliul Normal
Secreta NO
Este captusit cu inhibitori ai coagularii:
tPA si inhibitori ai trombinei
Secreta inhibitori ai agregarii
plachetare: prostaciclina si NO
Nu produce factori care promoveaza
marginatia (ECAM)
(ECAM),, astfel incat Leu nu
margineaza

NO
Responsabil pentru vasodilatatia endoteliuendoteliudependenta ajuta la controlul fluxului sanguin
si a stresului de frecare
Atenueaza adeziunea plachetara
Reduce cresterea SMC
Reduce producerea de endoteline
Impiedica formarea placii AS si vasoconstrictia

Iritanti ai endoteliului
LDLoxidate (reduceti aportul de lipide)
Homocysteina (cresteti aportul de acid
folic)
Fumatul productie de oxidanti (stop)
HPV, Chlamydia pneumonie
Radicali liberi R. (antioxidanti)
Trigliceride (antioxidanti, reduceti aportul )

Big Picture
1. [LDL] in s
1.
snge [LDL] in spatiul subendotelial
2. LDL se oxideaza devine iritant
3. Agentii propro-inflamatori (citokine) din musculatura si endoteliu,
NO scade
4. Citokinele stimuleaza numarului si macrofagelor in spatiul
subendotelial si transformarea lor in celule spumoase

5. Celulele spumoase se acumuleaza, exprima TF striuri lipidice,

miez lipidic
6. Celulele musculare netede formeaza un capison de colagen peste
miezul lipidic alcatuit din cristale de colesterol si celule
spumoase
7. Erodarea/subtierea capisonului fibros cu expunerea miezului
lipidic la agentii procoagulant din sange tromb obliterant
accidente vasculare acute

Placa de aterom vulnerabil

Fibrous cap
Media
Lumen
Area of
detail

Lipid
core

Vulnerable Plaque

Lumen

Th1 lymphocyte (IL-2, IFN-)

Lipid
core

Stable Plaque

Macrophage- > Foam cell (IL-6,MCP-1,TF +)

Activated intimal SMC (HLA-DR+)

- Normal medial SMC

Libby. Circulation 1995;91:2844-2850.

Markeri inflamatori in prognoza

evenimentelor cardiovasculare
Adipose tissue

Heart

Cytokines
Interleukin- 1 and 6
InterleukinTumor necrosis factor
PAI - 1

Troponin T and I
Creatine kinase MB
ICAM-1
ICAMVCAM--1 ,
VCAM
PAI - 1

IL-6

Liver

Vessel wall

Secretory
phospolipase A2
Macrophages

C-reactive protein
Fibrinogen
Serum amyloid A

ESR, WBC
Iron
Ab HSPs

CRP i RR pentru evenimente CV la

femei aparent sntoase WHS

Kluft C. et al. European Heart J 2004;6: C21C21-27

Strategii terapeutice
Dieta
Eliminarea factorilor
agravani
Medicamente

Scade LDL, Crete HDL

inte:
LDL < 100 mg %
HDL > 60 mg %
Dac colesterolul total < 150 mg%, LDL nu este factor
de risc
Indexul aterogen:
Total cholesterol / HDLHDL-C < 4.0
....este cel mai bun factor predictor
....cu ct este mai sczut, cu att mai bine

Efectul protector al HDL

1. Promoveaza efluxul colesterolului din
celulele spumoase
2. Inhiba oxidarea LDL
3. Inhiba eliberarea moleculelor de adeziune
(ECAM, VCAM) din celulele endoteliale
4. Indeparteaza excesul de colesterol din
sange si il transporta la ficat

How To Increase HDLHDL-C Levels

What Can Help?

Red wine/Beer (polyphenols, antioxidants)
Exercise (raises HDL)
Diet (15% cholesterol from consumption, 85%
made in body from Acetyl CoA)
Eliminate transtrans-fatty acids, saturated fats, high
glycemic foods
Increase: salmon, tuna, whole grain carbos,
vegetables, fruits, monounsaturated oils (olive,
canola)
Statins

Statins: Block the Formation of

Cholesterol in Liver from Acetyl CoA
HMG CoA Reductase inhibitors:
Acetyl CoA (from fatty acids
acids)) 3-OH
OH,3
,3-methylglutaryl CoA
HMG CoA Reductase
Mevalonate Cholesterol

Atorvastatin, Fluvastatin, Pravastatin, Lovastatin,

Simvastatin
For a given dosage, LDL is reduce most effectively:
A > S > L > P > F

HPS: Statin Benefit is Entirely

Independent of Baseline LDL
Risk ratio and 95% CI

Baseline LDL
(mM/l)

Statin
(10,269)

Placebo
(10,267)

< 2,6

282

358

2,6 3,4

668

871

1083

1356

3,5

All patients

2033
(19.8%)

2585
(25.2%)

Statin
better

Statin
worse

24% risk
reduction
(p<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Heart Protection Study Collaborative Group, Lancet 2002;360:7-22

Pleiotropic effects of statins

- mechanisms Acetyl--CoA
Acetyl
HMG--CoA Sintetase
HMG

3-hydroxi
hydroxi--3-methyl
methyl--glutaryl
glutaryl--CoA
(HMG--CoA)
(HMG
HMG--CoA Reductase
HMG

Mevalonate
Geranyl / Farnesyl PP

Isoprenylated small
GTP--binding
GTP
proteins
(e.g. Rho, Ras, Rac)

Dolichol Cholesterol Coenzyme Q10

STATINS

Statins... beyond cholesterol

- pleiotropic effects of statins
Haemostasis

Inflammation

t-PA
PAI 1
Platelet reactivity & TxA2 production

ROS, ox LDL, NFNF-kB

HLA DR, IFN - LyT
hs--CPR, TNFa, Fbg, ILhs
IL-6

Endothelial Cell
Endothelial Dependent Vasodilation
Superoxide (O2-) Production
Leukocyte Adhesion Molecule Expression

Smooth Muscle Cell

Growth Factor Production
Macrophage Stimulator
Production (M(M-CSF & MCPMCP-1)

Macrophage FoamFoam-Cell
Secretion of MatrixMatrix-Degrading Proteases
Release of Inflammatory Cytokines: ILIL-1, TNF
Tissue Factor Expression
modified after Rosenson et al. JAMA 1998;279:1643-1650.

PPAR regleaz expresia genelor

PPAR
implicate n metabolismul lipidic

Genele Apo A-I

i Apo A-II
Genele
enzimelor
- oxidrii

Gena LPL

Gena Apo C-III

Fenofibratul scade cantitatea de

LDL mici i dense
Fenofibrat
VLDL bogate n Apo C-III

VLDL srace n Apo C-III

TG
LDL mari, flotante

CE
CETP

CE

CETP

TG

LDL
LDL mici i dense

Receptor LDL
Macrofag

REVERSAL: Continuous Relationship Between

LDL, CRP and Percent Atheroma Volume
3.5
3
2.5
2
1.5

Change In Percent
Atheroma Volume (%)

1
0.5
0
-100

-75

-50
-25
0
Change In LDL-C (mg/dL)

25
3.5
2.5
1.5
0.5

Change In Percent
Atheroma Volume (%)

-0.5
-1.5
-2.5
-14 -12 -10 -8 -6 -4 -2
0
2
Change In CRP (mg/L)

Adapted from Nissen et al. N Engl J Med. 2005;352:29.

Nissen. Am J Cardiol. 2005;96(suppl):61F.

CRP vs. Number of Risk Factors:

PROVE IT
ITTIMI 22
Standard Therapy (Pravastatin 40)
Intensive Therapy (Atorvastatin 80)

4.0
3.5

CRP (mg/L)

3.0

P trend <0.0001
for each
Control of
risk factors:
factors:

2.5
2.0

1) BMI >25 kg/m2

1.5
1.0

2) Current
smoker
3) HDL <50 mg/dL

0.5

4) TG >150 mg/dL
5) Glucose >110 mg/dL

0.0

1
2
3
4
5
Number of Risk Factors

6) BP >130/85 mHg
7) LDL >70 mg/dL

Ray KK et al. J Am Coll Cardiol 2005;45:247A.

Cursul temporal potential al

efectelor Hipolipemiantelor
LDL-C
LDLlowered*

Inflammation
reduced

Endothelial
function
restored

Days
* Time course established

Vulnerable
plaques
stabilized

Ischemic
episodes
reduced

Cardiac
events
reduced*

Years

Caz nr. 1
Brbat, 37 ani

AHC: tatl cu moarte subit la 43 ani

AP: TA=135/80 mmHg
Glicemie=100 mg/dL
Colesterol total=420 mg/dL
LDL-col=315 mg/dL
HDL-col=35 mg/dL
Trigliceride=330 mg/dL

Caz nr. 2

Femeie, 58 ani

APP: obezitate, HTA, DZ tip II

Colesterol total=190 mg/dL
LDL-col=110 mg/dL
HDL-col=35 mg/dL
Trigliceride=298 mg/dL

Caz nr. 3
Brbat, 62 ani, normoponderal

TA=160/90 mmHg
Glicemie=105 mg/dL
Colesterol total=150 mg/dL
LDL-col=90 mg/dL
HDL-col=42 mg/dL
Trigliceride=815 mg/dL

Caz nr. 4
Brbat, 51 ani, fumtor, normoponderal

AP de efort
TA=130/90 mmHg
Colesterol total=172 mg/dL
LDL-col=100 mg/dL
HDL-col=25 mg/dL
Trigliceride=160 mg/dL

Caz nr. 5
Femeie, 40 ani, asimptomatic,
Supraponderal (IMC=29 kg/m2)
Colesterol total=230 mg/dL
LDL-col=150 mg/dL
HDL-col=44 mg/dL
Trigliceride=230 mg/dL