METABOLISME lemak

dan
patogenesis penyakit

Syazili Mustofa

BAGIAN BIOKIMIA
FAKULTAS KEDOKTERAN
UNVERSITAS LAMPUNG
1/3/17

SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
MEDICINE

1

Fungsi Lipid
1. Sumber energi potensial
2. Bantalan organ dalam / luar
3. Cadangan energi
4. Mempertahankan suhu tubuh / penyekat panas (sub
cutan)
5. Penyekat listrik (selubung myelin pada syaraf)
6. Struktur membran biologis
7. Struktur : susunan saraf
8. Pelarut Vitamin : A, D, E, K
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SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
MEDICINE

2

PENCERNAAN LIPID
* Mulut :
Lingual Lipase

TAG

* FA
pH : 3 – 6

* 1,2 DAG

* Lambung :
Gastric Lipase

TAG

* FA
pH : 3 – 6

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* 1,2 DAG

SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
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3

* Usus Halus
Pancreatic Lipase

TAG

* FA
* Gliserol
* 2.MAG
* 1.MAG

pH : 8

Kholesterol ester
hidrolase

Kholesterol ester

* Kholesterol
* FA

Posfolipase A2

Posfo-lipid

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* FA
* Liso-P-lipid
SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
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4

ABSORPSI LIPID LUMEN USUS GLISEROL 2. PORTA LISO POSFO LIPID ASIL KoA CE C CE TAG PL LISO. MAG FA : < C10 FA > C10 KHOL KHOL TAG V. MAG 1. MAG 1. P LIPID PL APO PROT KHILOMIKRON 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF SIRKULASI DARAH MEDICINE 5 . MAG FA : < C10 FA > C10 GLISEROL 2.

ABSORPSI TAG ABSORPSI TAG FA (C < 10) 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE FA (C < 10) 6 .

Malabsorbsi lemak merupakan kegagalan usus untuk menyerap jenis makanan berupa. Etiologi Defisiensi enzim pencernaan pankreas (lipase) . infeksi mikroorganisme. lembek. kerusakan lapisan mukosa usus. gangguan fungsi limfe dan empedu Manifestasi klinis : steatrrhea (tinja berwarna terang. jumlahnya sangat banyak dan terapung diair dan menempel dikloset) 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 7 . berbau busuk. lemak.

Pemeriksaan fecal fat (lemak feses) untuk mengetahui adanya malabsorbsi lemak. xeropthalmia Kekurangan Vitamin D : Penipisan tulang Kekurangan Vitamin E :kerusakan syaraf Kekurangan Vitamin K : Mudah memar atau mudah mengalami perdarahan Pemeriksaan Diagnostik Radiologi: USG atau foto polos abdomen untuk mengidentifikasi adanya kalsifikasi pancreas. pemeriksaan absorbsi pancreas. dan steathorea. B12. Pemeriksaan laboratorium lain yaitu pemeriksaan fungsi pancreas. Penyerapan lemak dan vitamin larut lemak menjadi berkurang Kekurangan Vitamin A :gangguan visus. pemeriksaan toleransi xylose.Akibatnya…. Pemeriksaan biopsy usus halus untuk mengetahui penyebab lesi usus. pemeriksaan absorbsi vit.. pemeriksaan asam empedu pernafasan. diare kronis. 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 8 .

Khilo-thoraks * Fistula antara pembuluh lymph dengan rongga pleura * Rongga pleura berisi cairan putih. seperti air susu * Therapi : Operatif 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 9 .ASPEK KLINIK 1. KHILURIA * Fistula antara pembuluh lymph dengan saluran air seni * Kebocoran lemak (khilomikron) pada urine * Urine berwarna putih susu Segera sesudah makan / absorpsi * Therapi : Operatif 2.

96 > 400 1 99 88 8 3 1 ….125 – 1.019 – 1.063 – 1. ? Intestine HDL 2 1. Very low density lipoproteins (VLDL) Liver and intestine 0.210 57 43 13 46 29 6 6 > 1.063 0–2 Low density lipoproteins LDL 1 Liver and intestine LDL2 High density lipoproteins HDL 1 * Liver. HDL 3 1.063 2– 12 21 79 13 28 48 10 1 1.006 – 1.125 33 67 16 43 31 10 ….Lipid Transport & Metabolism of Lipoprotein Composition of the lipoproteins in plasma of man Composition Fraction Source Density Sf Percentage of Total Lipid Prot ein (%) Total Lipid (%) Trig lyce ride Phos pholi pid Chol ester ol ester Chole sterol (Free) Free Fatty Acids Chylomicrons Intestine < 0. SYAZILI1960 MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF 1/3/17 MEDICINE 10 ..2810 99 1 0 0 0 0 100 Albomin-FFA Adipose tissue Adapted from Olson & Vester.96 – 1.006 20 – 400 7 93 56 20 15 8 1 1.019 12 – 20 11 89 29 26 34 9 1 1.

Separation of Lipoprotein : By Ultrasentrifugation Chylomicron VLDL LDL HDL FFA-albumin compleks 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 11 .

96 Chylomicrons 1.006 (VLDL) -Lipoproteins Pre--Lipoproteins -Lipoproteins 1.Density Origin < 0.063 (LDL) < 1.063-1.21 (HDL) + 1/3/17 Separation SYAZILI of plasma lipoproteins by MUSTOFA BIOCHEMISTRY electrophoresis on DEPARTEMENT UNILA FACULTY OF MEDICINE Agarose gel 12 .006-1.

Metabolism of Chylomicron 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 13 .

Metabolisme of VLDL 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 14 .

Fatty Liver 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 15 .

1/3/17 TAG terakumulasi dalam hati SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 16 .meningkatnya mobilisasi lemak dari jaringan adiposa.meningkatnya hidrolisa lipoprotein triasil gliserol oleh lipoprotein lipase dalam jaringan ekstra hepatik . seperti terjadi pada kelaparan dan DM yang tidak terkontrol .Alkoholism kronis FFA liver produksi VLDL Produksi VLDL tidak dapat mengimbangi influx FFA ke dalam hati fatty liver. disebabkan karena : . Meningkatnya FFA plasma.Fattty Liver Disebabkan Oleh : 1.

Blokade metabolisme dalam produksi lipoprotein plasma : . metionin.kegagalan penyediaan posfolipid yang ditemukan dalam lipoprotein : * defisiensi lipotropic faktor : cholin.blokade dalam biosintesa apoprotein : puromycin. betain .blokade biosintesis lipoprotein dari apoprotein + lipid : CCl4. ethionin. asam orotat .2.kegagalan dalam mekanisme sekresi LP 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 17 . CCl4 .

1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 18 .

1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 19 .

1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 20 .

TAG Metabolism 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 21 .

Pathway by which glycerol derived from TAG enters glycolysis 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 22 .

Metabolisme Jaringan Lemak 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 23 .

Regulasi Lipolisis Dalam Jaringan Adiposa 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 24 .

Fatty Acids Metabolism Fatty Acids Transport from Sitoplasm to Mitochondria O R I ntermembrane space O C S-CoA R Carnitine O R Carnitine CoA-SH O R C CoA-S Carnitine Carnitine acyltranferase I 1/3/17 S-CoA Carnitine C C Matrix SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 25 .

CoA C4 Acetyl .ydroxyacyl-CoA R  CH 2 dehydrogenase  CH 3  C || || O O (C14) Acyl-CoA (myristoyl-CoA) (a)  CoA NAD+  S  CoA Acetyl .CoA |  C  CH 2  C  S  CoA || | O H C14 Acetyl .CoA Acetyl .r 2Enoyl-CoA FADH 2 C  S  CoA acyl-CoA || dehydrogenase O R  CH 2  C | H  C  C  S  CoA | || H O enoyl-CoA hydratase NADH+H+ β-Ketoacyl .CoA C6 Acetyl .CoA C12 Acetyl .CoA (b) 26 .CoA C10 Acetyl .CoA C8 Acetyl .CoA SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE H2O OH L-β-Hydroxy acyl .Beta Oksidation Palmitoyl-CoA FAD (C16) β α R  CH 2  C H2  CH2  trans.CoA R  CH2  C  CH 2  C  S  CoA || || O O acyl-CoA acetyltransferase (thiolase) CoA-SH  CH2  S R  C 1/3/17 βh .

β-UNSATURATED 2CO2 4 3~ P NADH+H+ Respiratory chain CoA. β-HYDROXYACYL-CoA ENOYL HIDRASE Fp H2 (TRANS) H2O . β-HYDROXYACYLCoA DEHYDROGENASE 2 2~ P H2O CITRIC ACID CYCLE 5 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF ACYL-CoA THIOLASE MEDICINE β-KETOTHIOLASE ACETYL-CoA 27 .β-Oxidation of fatty acids FATTY ACID (FFA) ATP ACYL-CoA (ACTI VE FATTY ACI D) AMP+PPi Mg++ CoA.SH β-KETOACYL-CoA 1/3/17 Respiratory chain ACYL-CoA NAD+ L(+).SH Thiokinase 1 Fp (Flavoprotein) ACYL-CoA DEHYDROGENASE H2O 3 L(+).

 -Oksidasi Asam
Lemak Tidak Jenuh

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SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
MEDICINE

28

O x i d a t i o n o f P r o p i o n i l CoA
Propionyl-CoA H
H
O
|
|
||
H  C  C  C
|
|
|
H
H
S  CoA

Propionyl-CoA
carboxilase

HCO-3
ATP

H
H
|
|
H  C  C
|
|
C
H
O

Succinyl-CoA

C
-O

S CoA

Methylmalonyl-CoA
mutase

Coenzime B12

biotin

O

AMP+PPi
D-Methylmalonyl-CoA

H
H
O
|
|
||
Methylmalonyl-CoA
H  C  C  C
epimerase
|
|
H
S  CoA
C
-O

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H
H
|
|
H  C  C
|
|
H
C
O

O
SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
MEDICINE

L-Methylmalonyl-CoA

O
C
-O
S

CoA

29

Three stage of
fatty acid
oxidation

1/3/17

SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
MEDICINE

30

Energi yang dihasilkan dari oksidasi 1 mol palmitat :
- 7 x  oksidasi

35 ATP

- 8 mol asetyl KoA (TCC)

96 ATP
131 ATP

Energi yang diperlukan
(1 ATP aktivasi + 1 ATP mema-

2 ATP –
129 ATP

Suki mitochondria)

1/3/17

SYAZILI MUSTOFA BIOCHEMISTRY
DEPARTEMENT UNILA FACULTY OF
MEDICINE

31

Regulasi Oksidasi Asam Lemak Dalam Hati BLOOD Carbohydrate FFA LIVER FFA Acetyl-CoA ACETYL-CoA CARBOXYLASE Glucagon Malonyl-CoA Palmitat VLDL Acyl-CoA Esterification Insulin Cytosol CARNITINE PAMITOYL TRANSFERASE Acyl-CoA Mitochondrion Mit o me chond mb ran rial e -Oxidation Acetyl-CoA Ketogenesis Ketone bodies 1/3/17 Acylglycerol SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE CO2 32 .

Ketone Bodies 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 33 .Metab.

Synthesis and Utility of 1/3/17 Ketone Bodies SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 34 .

Ketogenesis in The Liver 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 35 .

Ketogenesis in The Liver 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 36 .

REGULASI KETOGENESIS Triasylglycerol 1 ADIPOSE TISSUE Lipolysis FFA BLOOD FFA LIVER CPT-I gateway Acyl-CoA 2 Esterification -Oxidation Acylglycerols Acetyl-CoA Ketogenesis 3 Citric acid cycle CO2 1/3/17 KetoneBIOCHEMISTRY bodies SYAZILI MUSTOFA DEPARTEMENT UNILA FACULTY OF MEDICINE 37 .

Aseto Asetat Ko-A transferase Aseto Asetat Aseto asetil-KoA Suksinil-KoA Suksinat Thiolase Aseto asetil-KoA Asetil-KoA TCC 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 38 .KATABOLISME KETON BODIES DALAM JARINGAN EKSTRA HEPATIK 1.

Aseton : sulit dioksidasi 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE TCC 39 .2. Hidroksi Butirat D(-)-OH-butirat dehidrogenase D(-) Hidroksi Aseto asetat butirat NAD+ NADH + H+ Aseto asetil-KoA Asetil-KoA 3.

KETOSIS (KETOASIDOSIS) Terjadi pada : 1. Diabetes Mellitus Kegagalan pemenuhan kebutuhan energi dari KH (glukosa) 1/3/17 Lipolisis FFA SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE -oksidasi 40 .

-HEPATIK) KETO-ASIDOSIS TCC 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 41 .FFA -oksidasi KHOLESTEROL ASETIL-KoA HMG-KoA reduktase HMG-KoA HMG-KoA liase TCC KETON BODIES ASETIL-KoA (JARINGAN EKS.

KELAPARAN * Glukosa dioksidasi hanya untuk keperluan eritrosit dan susunan syaraf pusat ( CNS ) yang sangat tergantung pada glukosa * Keperluan energi diambil dari cadangan lemak * Lipolisis 1/3/17 FFA -oksidasi SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 42 .2.

-HEPATIK) KETOSIS RINGAN TCC 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 43 .FFA -oksidasi ASETIL-KoA KHOLESTEROL HMG-KoA TCC KETON BODIES ASETIL-KoA (JARINGAN EKS.

Diet Tinggi Lemak Pantang Karbohidrat * Sama dengan kelaparan 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 44 .3.

Fatty Acid Synthesis 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 45 .

ATHEROSCLEROSIS DAN PENYAKIT JANTUNG * Atherosclerosis A. Coronaria coronary heart disease ( CHD ) * Sclerosis coroner biasanya berhubungan erat dengan kadar kholesterol dan TAG darah Normal kadar Kholesterol : 150 – 200 mg% > 200 – 240 > 240 Borderline Hiperkhol-emia Normal kadar TAG : 150mg% 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 46 .

Kholesterol (LDL) N.(TAG (VLDL) .Kholesterol (LDL) .Hipothiroidi .Banyak makanSYAZILI lemak / karbohidrat MUSTOFA BIOCHEMISTRY 1/3/17 DEPARTEMENT UNILA FACULTY OF MEDICINE 47 . TAG (VLDL) N . TAG (VLDL) * Yang lebih penting lagi adalah : Ratio LDL-Khol / HDL-Khol LDL-Khol Normal <3 HDL-Khol * Hiperkhol-emia : .Familial hiperkhol-emia .Kholesterol (LDL) .* Ada 3 kemungkinan pada atherosclerosis : .Diabetes Mellitus .Kurang olah raga .

1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 48 .

Syazili mustofa PATHOGENESIS OF ATHEROSCLEROSIS syazili mustofa Department of Biochemistry School of Medicine. lampung University .

thickened inner layer (fatty deposits & fibrous tissue)  hardening of the arteries .involves coronary & cerebral vessels  myocardial infarctions & strokes  majority of deaths in industrialized countries  additional killer disease in developing countries .disease of muscular arteries .syazili mustofa Atherosclerosis: .

control hypertension .recurrence prevention . saturated fat) .50 %.diet (cholesterol.syazili mustofa Atherosclerosis: significant progress in health impact  death IHD .smoking .prevention :.70%  increase life expectancy 5 years due to : . strokes .improved treatment methods .change habbits .

ischemic vital organ • progress insidiously -.syazili mustofa Atherosclerosis: • developes over decades -.large lesion -.clinically apparent -.incidence of death due to IHD .begin in childhood • initially symptomless -.beyond the reach to intervene successfully • epidemiologic data -.

uncertain.syazili mustofa Risk factors for atherosclerosis Major Lesser. or non- quantitated Non-modifiable Obesity Increasing age Male gender Family history Physical inactive (type A personality) Stress Homocysteine Genetic abnormalities Postmenopausal estrogen deficiency High carbohydrate intake Potential Controllable Lipoprotein(a) Hyperlipidemia Alcohol Hypertension Cigarette smoking Diabetes Hardened (trans) unsaturated fat intake Chlamydia pneumoniae Multiple risk factors may impose more than an additive effect .

7 38 36.5 56.5 23.2 13.4 30 28.syazili mustofa 57.5 Estimated 10 Year Risk of Ischemic heart Disease 70 BP Systolic 120 160 160 160 160 160 160 Cholesterol 220 220 260 260 260 260 260 HDL-C 50 50 50 35 35 35 35 Diabetes - - - - + + + Cigarettes - - - - - + + 10 0 .8 w omen 40 8.7 20 16.8 27.7 5.3 9.4 60 50 men 17 11.

syazili mustofa Atherogenesis: response to injury hypothesis specialized protective form inflamatory fibroproliferative response to repeated insult excessive  distinct disease process .

1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 56 .

syazili mustofa Hyperlipidemia. Hypertension.MCP-1) + Extracellular matrix system Foam cells Lipid uptake Oxidized LDL Proliferation of smooth muscle cells Intima Extracellular lipids and necrotic cells Cytokines/Growth Factors Internal elastic membrane Migration of smooth muscle cells Smooth muscle cells Media Normal Vessel Progressive development of Artherosclerotic plaque . Smoking. Toxins. factors.IL-1. Viruses Endothelial Injury/Dysfunction Monocyte adhesion and emigran into intima Lumen Cholesterol efflux via HDL LDL Endothelium Macrophage LDL Cytokines (e. Immune reactions. Hemodynamic.g..

SMC . platelets .circulating monocytes.lipoproteins .monocyte adhesion & infiltration .lipid accumulation & oxidation .SMC proliferation .arterial EC.chemical mediators • chronic inflamatory response • multiple mechanism : .EC dysfunction .extracellular matrix deposition & thrombosis .key steps identified • involves & interacts: .syazili mustofa Atherogenesis • incompletely understood -.

non thrombogenic & non leukocyte adherent .syazili mustofa Primary event in atherogenesis is “injury to arterial EC Normal EC : .manifest before lesion apparent .source of growth regulatory molecules .altered vasoactive release .impairment of permeability barrier .source of vasoactive (EDCF & EDRF) .interference normal antithrombotic .permeability barrier .synthesizes connective tissue matrix altered by substance related to risk factors EC dysfunction : .affects underlying SMC .

Hemodynamic disturbances 2. Hypercholesterolemia Once EC surface denuded  unable to repair injured site Once EC layer lost  thrombogenic  SMC. foam cells & others exposed to blood .syazili mustofa What initiates EC dysfunction in early atherosclerosis ? 1.

increased LDL permeability .alteration of vasoactive production .syazili mustofa Stages : .produce more procoagulant materials .oxidized LDL .recruitment of monocytes & T-lymphocytes . VCAM-1) .produce growth factor  stimulate SMC & macrophage .produce glycoprotein molecule(ICAM-1.

syazili mustofa EC injury requires loss of EC structure ? Structural disruption does not necessary developing lesion lipid accumulation monocytes infiltration occur through intact EC surface relay on specific biochemical modifications and cellular signaling pathways rather than structural disruption of EC layer .

syazili mustofa Laminar shear stress typically encountered in lesion protected areas Induces EC genes (atheroprotective genes) to product SOD Protect from lesion development Nonrandom localization of early atherosclerotic lesion .

syazili mustofa EC dysfunction  no longer effective barrier  increased permeability  increased LDL infiltration  LDL accumulation within intima  LDL trapping  chemical modification modified LDL  oxidized by local free radicals or enzymatically modified  by ECs and macrophages Ox-LDL  chemoattractant for monocytes  scavenged by macrophages .

syazili mustofa Hyperlipidemia contribution to atherogenesis : • impair EC function  free radicals production  deactive NO  activates NF-B  expresses cytokines • lipoprotein accumulation .

syazili mustofa Ox-LDL formation  scavenged by macrophages  chemotactic for monocytes  induce adhesion molecules  monocytes adhesion  inhibits macrophage motility  stimulates cytokines & GF release  cytotoxic to EC & SMC  immunogenic Antioxidants & lipid lowering drug  improve EC function  prevent atherogenesis .

ET-1) * EC expression of adhesion molecules (ICAM-1. VCAM-1. MCP-1.syazili mustofa LDL infiltration & modification  Leukocytes attraction (monocytes & T-lymphocytes) Due to : * chemotactic activity of mLDL * EC expression of cytokines (TNF-. P-selectin) .

syazili mustofa Macrophages roles in atherogenesis : • IL-1 & TNF- production  increase leukocytes adhesion  further leukocytes recruitment into plaques • toxic oxygen species production  LDL oxidation  EC injury • elaborate growth factor  SMC proliferation • scavenged Ox-LDL  foam cells formation .

syazili mustofa T-lymphocytes • stimulated by IL-2 from macrophages • produce cytokines & growth factors  activate macrophages • relative small fraction • precise stimuli uncertain • suggest immune component involvement in atherogenesis .

syazili mustofa SMC proliferation within intima  critical event in lesion progression SMC contribution in atherogenesis : synthesize connective tissue matrix accumulate lipid  foam cells formation SMC : contractile & synthetic types relevance to respond in atherogenesis .

Ang-II. PGE.syazili mustofa Contractile phenotype • myofilament rich • responsive to vasoactive substances  ET-1. etc • predominant in adult Synthetic phenotype • myofilament poor • rich in RER & Golgi complex • capable in expressing genes  cytokines & growth regulating molecules • synthesize extracellular matrix . NO.

foam cells & platelets) (inhibits by heparine like molecules)  take up lipids  foam cells formation  aggregates into fatty streaks  development of fibrous cap  fibrous plaques formation  advanced atherosclerotic lesions Hypercholesterolemia ameliorated  fatty streaks regress .syazili mustofa Early lesion evolution  SMCs migrate & gather in intima  proliferate (induced by substance from EC.

anucleated hemostasis in vessel injury inappropriate activation  atherosclerosis capable very little protein synthesis source of growth stimulatory molecules (PDGF. disk shape. TGF-) .syazili mustofa Platelets : small.

syazili mustofa Signal Plasma membrane Phospholidis G protein Phospholipase Phosphatidylinositols Recept or Cytoplasm Arachidonic acid Prostaglandins Inositol trisphosphate Diacylglycerol Protein kinase C activity or Enzyme activities Modulate cell response or Metabolic pathway Ca++ Endoplasmic reticulum .

Oxidative modification hypothesis Oxidative modification of LDL as key factor initiating and developing atherosclerosis High plasma LDL  increased LDL in intima  increased LDL deposit  may have been modified by EC  interact w/ macrophages & SMCs  increase ox-LDL geometrically  attract more monocytes & toxic to EC .syazili mustofa Other theories of atherogenesis 1.

syazili mustofa Other theories of atherogenesis 2. Monoclonal hypothesis • Intimal proliferative lesions result from the multiplication of single SMC • Mitogenic or mutagenic factors stimulate single SMC proliferation • Plaques may be equivalent to benign neoplastic growth induced by exogenous chemical .

Focal senescence theory • Intrinsic aging processes contribute to atherogenesis • SMC proliferation under feedback control • Feedback control system tends to fail w/ age as cells die and not adequately replaced 4. Lysosomal theory • • Altered lysosomal function  atherogenesis • Generalized degradation of cellular components requires continuing renewal of lysosomal enzymes • Deficiency lysosomal activity  increased lipid deposition  lipofuscin accumulation  atherosclerosis .syazili mustofa Other theories of atherogenesis 3.

hematoma From fourth decade Clinically silent or overt . or mainly calcific.syazili mustofa Nomenclature and main histology Sequences in progression Type I (initial) lesion Isolated macrophages Foam cells I Type II (fatty streak) lesion Mainly intracellular Lipid accumulation II Type III (intermediate) lesion Type II changes and small Extracellular lipid pools III Type IV (atheroma) lesion Type II changes and core of Extracellular IV Main growth mechanism Earliest onset Clinical correlation From first decade Clinically silent Growth mainly by lipid accumulation From third decade Type V (fibroatheroma) lesion Lipid core and fibrotic layer. Hematoma-hemorrhage. or Multiple lipid cores and fibrotic Layers. thrombus VI Accelerated smooth muscle and collagen increase Thrombosis. Or mainly fibrotic V Type VI (complicated) lesion Surface defect.

syazili mustofa Fatty streak Fibrous plaque Complicated lesion Calcification Plaque ruptue Rigidity of vessel wall Thrombosis Hemorrhage into plaque Fragmentation Weakening of vessel wall Narrowing of lumen Emboli Aneurysm .

syazili mustofa Fibrofatty atheroma Lipid debris Lymphocyte Collagen .

syazili mustofa Atherosclerosis • muscular arteries disease • thickened inner layer by fatty deposits & fibrous tissue • killer disease • mechanisms remain elusive & incompletely understood • progress insidiously for many years before symptoms develop • difficult to track early development • difficult to relate severity to lesions type • risk faktors identification depend upon its relation to clinical symptoms than to extent & severity .

syazili mustofa Pathogenesis • response-to-injury hypothesis • specialized protective form • defense mechanism gone awry • inflamatory fibroproliferative response to repeated / continue insult • involves & interacts vessel wall cells & circulating blood elements • pathological hallmarks fatty streaks & atheroplaques .

Nayah nayah trimo kasi 1/3/17 SYAZILI MUSTOFA BIOCHEMISTRY DEPARTEMENT UNILA FACULTY OF MEDICINE 83 .