Biochemistry Lipoprotein

7/30/2019 Biochemistry Lipoprotein

1/84

BY

Dr.Liniyanti D.Oswari, MNS, MSc.


2/84

To understand the lipid & lipoproteinmetabolism in the body.

Recognize the significance of dyslipidemia inAtherosclerosis on CVD & CHD, including therole of HDL-C as a protective risk factor forCVD &CHD

Recognize the relationship dyslipidemia with

central obesity & Insulin resistance Examine recent clinical trials of dyslipidemia

as it relates to the prevention and treatmentof CVD & CHD


3/84

Clusters of lipids associated withproteins that serve as transport vehiclesfor lipids in the lymph and blood


4/84

Chylomicrons

VLDL Very low density lipoprotein

IDL Intermediate densitylipoprotein

LDL Low density lipoprotein

HDL High density lipoprotein


5/84

Distinguished by sizeand density

Each containsdifferent kinds andamounts of lipids andproteins

The more lipid, thelower the density

The more protein, thehigher the density


6/84

Class Size (nm) Lipids Major

Apoproteins

Chylomicra 100-500 Dietary TG B-48,C-II,E

VLDL 30-80 EndogenousTG

B-100,C-II,E

IDL 25-50 CEs & TGs B-100, E

LDL 18-28 CEs B-100

HDL 5-15 CEs A,C-II,E

Lp (a) 25-30 CEs B-100 &glycoproteins


7/84

Lipid Chylomicron VLDL IDL LDL HDL

Cholesterol 9 22 35 47 19

Triglyceride 82 52 20 9 3

Phospholipid 7 18 20 23 28


8/84


9/84

Made by intestinal cells Most of lipid is triglyceride

Little protein ApoA-I, ApoA-II, ApoB-48, ApoC

Deliver fatty acids via lipoprotein lipase

Chylomicron remnants Lipoprotein particle that remains after a

chylomicron has lost most of its fatty acids Taken up by liver

Contents reused or recycled


10/84

Liver Synthesizes & metabolizes lipids

Central command center for relation of lipidmetabolism

Makes additional lipoproteins


11/84


12/8412


13/8413


14/84

Vessel wallCholestAA

FA

P,

glycerol


15/84


16/84

Liver

Fecal bile acidsand neutralsterols

Exogenous

Extrahepatic

tissues

Endogenous

Dietarycholesterol

(~300700 mg/day) Intestine

Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbookof Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. InHarrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J

Suppl2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.

Biliary

cholesterol(~1000 mg/day) ~700 mg/day

Synthesis(~800 mg/day)


17/84

Cholesterol is obtained from endogenous and exogenoussources. Endogenous cholesterol is synthesized in all tissues,but primarily the liver, intestine, adrenal cortex, and reproductivetissues, including the placenta. Exogenous cholesterol isabsorbed by the intestine from dietary and biliary sources and

transported to the liver.1,2 In individuals eating a relatively low-cholesterol diet, the liver produces about 800 mg of cholesterolper day to replace bile salts and cholesterol lost in the feces.2Depending on diet, people typically consume 300 to 700 mg ofcholesterol daily.3,4 Approximately 1000 mg of cholesterol issecreted by the liver into the bile. Thus, approximately 1300 to

1700 mg of cholesterol per day passes through the intestines,4of which about 700 mg per day is absorbed.5 Because plasmacholesterol levels are maintained within a relatively narrow rangein healthy individuals, a reduction in the amount of dietarycholesterol leads to increased synthesis in the liver andintestine.2


18/84

1000 mg

Resins

Plant stanols NPC1L1(Ezetimibe)

Inhibitors


19/84

Cholesterol that is absorbed from the intestinal lumencomes from two sources: dietary cholesterol andbiliary cholesterol (which is by far the greater of the

two in quantity). Cholesterol is emulsified by bile acids and packaged

in lipid micelles.

These lipid micelles are transported to the brush

border of jejunal enterocytes. At the brush border of the enterocyte, the cholesterol

is released from the lipid micelle and then enters theenterocyte.


20/84

Made by liver Contains large amounts of triglyceride

Delivers fatty acids to cells

More dense than chylomicrons A bit more protein (8%)

ApoB-100, ApoC, ApoE


21/84


22/84


23/84

1- Assembly andsecretion

2- Hydrolysis by LPL

3- Direct uptake byhepatocyte

4- Flux of pathway

into LDL

3

1

2

4


24/84

Lipoprotein that results from loss of fattyacids from VLDL

Major lipid is cholesterol esters

Proteins similar to VLDL but greaterpercentage (15%) ApoB-100, ApoC, ApoE

Taken up by liver or remain in circulation

Converted to low-density lipoproteins (LDL)


25/84

Bad cholesterol; major lipid in LDL Delivers cholesterol from liver to cells

Cell membranes Hormone production

Protein (21%) ApoB-100 Binds to specific LDL receptor

LDL receptors Membrane-bound proteins that bind LDL,

causing them to be taken up & dismantled


26/84

Increase LDL SFAs

Transfatty acids

High cholesterol

intake Lifestyle factors

Genetics

Decrease LDL High PUFA diet

-3 fatty acids

Dietary fiber

Lifestyle factors Genetics


27/84


28/84

Insulin resistanceincreased NEFA andglucose flux to liver

Insulin resistanceand decreasedapo-Bdegradation

InsulinresistanceanddecreasedLPL

IR impairs

LDLR

IncreasedVLDL

FCHL

DM II

Metabolicsyndrome


29/84

Direct Association Longer residence time inplasma than normal sizedLDL due to decreasedrecognition by receptors inliver

Enhanced interaction withscavenger receptorpromoting foam cellformation

More susceptible tooxidation due to decreasedantioxidants in the core

Enter and attach more easilyto arterial wall

Endothelial cell dysfunction

IndirectAssociation Inverse relationshipwith HDL Marker for atherogenicTG remnantaccumulation Insulin resistance


30/84

Good cholesterol; major lipid isphospholipid Lipoprotein made by liver that circulatesin the blood to collect excess cholesterol

from cells Lowest lipid-to-protein ratio Protein (50%) ApoA, ApoC, ApoE

Reverse cholesterol transport Salvage excess cholesterol from cells Transported back to liver


31/84


32/84

HMG-CoA reductase-reduces HMG-CoA to mevalonicacid in the rate-limiting step of cholesterolbiosynthesis (mainly liver and intestine)

Lipoprotein Lipase- digests TG core of CMC and VLDL

Hepatic Lipase-conversion of IDL to LDL

CETP-transfers cholesteryl esters from HDL to otherlipoproteins in exchange for TG LCAT(lecithin cholesterol acyl transferase) conversion

of cholesterol to cholesterol esters Apolipoprotein A-major protein of HDL activating

many reactions Apo-B-major protein of VLDL, IDL, and LDL

Apo-CII and Apo E obtained from HDL by CMC andVLDL for activation of LPL and receptor recognitionrespectively


33/84


34/84

Why Does HDL-C Protect?

HDL-C

Protection againstoxidation

Modulation ofendothelial function

Protection of the vessel wall

Cholesterol

acceptor

Cholesterylester

donor

Reverse Cholesterol

Transport (RCT)

Endothelial repair

Anti-thrombotic

Anti-inflammatory


35/84

What raises HDL? Uncertain if low carbohydrate diets offer

protection

High MUFA intake

Lifestyle factors ( Exercise)

Genetic factors influence HDL


36/84

Reverse cholesterol transport

Maintenance of endothelial function

Protection against thrombosis

With Apo A-I inhibits generation of calcium-induced procoagulant activity on erythrocytesby stabilizing cell membrane

Low blood viscosity via permitting red celldeformability

Anti-oxidant properties-may be related toenzymes called paraoxonase


37/84

Elevated triglycerides

Post-prandial lipemia

Small dense LDL (type B)

Elevated LDL

Low HDL cholesterol

Elevated Total

Cholesterol

Nature Medicine 2002


38/84

Fat Cells

TG

Apo B

VLDL

Liver

IR

Insulin

FFA

CE (CETP) TG

(lipoprotein

or

hepatic lipase)

Kidney

Apo A-1

VLDL

LDL

CE

(CETP)

TG

HDL

SD

LDL

(hepatic lipase)


39/84

Increased Apo B Triglycerides VLDL LDL and SmallDense LDL

Decreased HDL Apo A-I


40/84


41/84

VLDL1 gives rise tosmall dense LDL

Increase TG/Chol

content throughCETP

Increasedelipidation by

hepatic lipase


42/84

HDL-3, larger with apoA, C-II, & C-III

HDL-2, largest, withadditional apo E.

Best negative correlateCAD

Other functionsattributed to HDL:inhibits monocyte

chemotaxis, LDLoxidation

Tulenko 2002 J Nuclear Cardiology 9:638


43/84


44/84

CETPinhibitors

Low HDL-cholesterol

Increased catabolism of small dense HDLLow HDL cholesterol by both content and #particles


45/84

High triglycerides

Post-prandiallipemia

Small dense LDL(type B)

Low HDLcholesterol

ABCA-1

CETP

Niacin

Statin

Fibrate


46/84

Familial Hypercholesterolemia High LDL-C(Type IIA)

Polygenic Familial Hypercholesterolemia Familial Combined Hyperlipidemia High LDL-

C and/or high TG levels Familial Dyslipidemias High TG and low HDL

Familial Dysbetalipoproteinemia (Type III)


47/84

Type Lipoprotein ElevationI ChylomicronsIIa LDLIIb LDL + VLDLIII IDL (LDL1)IV VLDLV VLDL + Chylomicrons

47

IDL, intermediate-density lipoproteinLDL, low-density lipoproteinVLDL, very-low-density lipoprotein

Fredrickson-Levy-Lees Classification

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com

Lipid Phenotype Plasma Lipid Levels Lipoprotein PhenotypeClinical Signs


48/84

[mmol/L (mg/dL)] Elevated Isolated hypercholesterolemiaFamilialhypercholesterolemia

Heterozygotes TC =713 (275500)

LDL IIa Usually developxanthomas in adulthoodand vascular disease at3050 years

Homozygotes TC>13 (>500)

LDL IIa Usually developxanthomas in adulthoodand vascular disease inchildhood

Familial defective

Apo B-100

Heterozygotes TC =

713 (275500)

LDL IIa

Polygenichypercholesterolemia

TC = 6.59 (250350)

LDL IIa Usually asymptomaticuntil vascular diseasedevelops; no xanthomas

Isolated hypertriglyceridemiaFamilial

hypertriglyceridemia

TG = 2.88.5 (250

750)

VLDL IV Asymptomatic; may be

associated with increasedrisk of vascular disease

Familial LPLdeficiency

TG >8.5 (750) Chylomicrons, VLDL

I, V May be asymptomatic;may be associated withpancreatitis, abdominalpain,hepatosplenomegaly

Familial Apo C-II TG >8.5 (>750) Chylomicron I, V As above 48DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com

Lipid Phenotype Plasma Lipid Levels Lipoprotein Phenotype Clinical Signs


49/84

[mmol/L (mg/dL)] ElevatedHypertriglyceridemia and hypercholesterolemiaCombined

hyperlipidemia

TG = 2.88.5 (250

750); TC = 6.513(250500)

VLDL, LDL IIb Usually asymptomatic

until vascular diseasedevelops; familialform may present asisolated high TG orisolated high LDLcholesterol

Dysbetalipo-

proteinemia

TG = 2.88.5 (250

750); TC = 6.513(250500)

VLDL, IDL;

LDL normal

III Usually asymptomatic

until vascular diseasedevelops; may havepalmar ortuboeruptivexanthomas

49DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com


50/84

Many genetic abnormalities & environmentalfactors lead to lipoprotein abnormalities

Current laboratory values can not defineunderlying abnormality

2 hyperlipidemia should be initiallymanaged by correcting underlyingabnormality when possible

50 50


51/84

Genetic disorder resulting in production offaulty HDL particles that cannot take upcholesterol from cells

High risk for developing cardiovascular

disease

Can see the platelet


52/84

Image courtesy of the Internet Stroke Center at Washington University - www.strokecenter.org

aggregation in response to thefoam cell chemicals and tissuedamage

The platelets will activate thecoagulation cascade, resultingin the production of fibrinstrands which trap platelets,

red and white blood cells overthe area = thrombusIn larger vessels, it takeslonger to develop a thrombusbig enough to completely

block the vessel so you getwarning signs (TIA, UA) ofstroke and MIThis process happens

everywhere (brain, heart)


53/84

Image courtesy of the Internet Stroke

Center at Washington University -www.strokecenter.org


54/84

General term for all diseases of the heart and

blood vessels Atherosclerosis is the main cause of CVD

Atherosclerosis leads to blockage of bloodsupply to the heart, damage occurs (coronaryheart disease, CHD) Cardio = heart Vascular = blood vessels

Lipoproteins and cardiovascular disease

(CVD) risk- LDL is positively associated with CVD

- HDL is negatively associated with CVD


55/84

Age

Men: 45 years

Women: 55 years or premature menopause without estrogen replacementtherapy

Family history of premature CHD (definite myocardial infarction or sudden

death before age 55 years in father or other male first-degree relative, orbefore age 65 years in mother or other female first-degree relative)

Cigarette smoking

Hypertension (140/90 mm Hg or taking antihypertensive medication)

Low HDL cholesterol (60 mg/dL counts as "negative" risk factor; its presence removes one riskfactor from the total count.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7thEdition: http://www.accesspharmacy.com


56/84

Athrogenesis

MVS 110: Lecture #11


57/84

1. Vasodilatory Endothelial Dysfunction:Brachial Ultrasound Flow-Mediated Dilation.

2. Atherosclerosis Burden/End-organ Damage:Carotid IMT, # plaques (based on carotid US),

IVUS, EBCT, advanced CT, MRI3. General Inflammatory Marker:

hs-C Reactive Protein

4. Markers of Inflamed Endothelium:ICAM, VCAM, e-Selectin, vWf

5. Other: Homocysteine


58/84

Libby et al. Circulation2002;105:1135-1143.

E-Selectin,P-Selectin

LDL

OxLDL

L-Selectin,Integrins

VCAM-1,

ICAM-1

M-CSF

MCP-1

MacrophageActivation & Division

Monocyte

Intima

Media

Smooth Muscle CellMigration

Otherinflammatory triggers


59/84

Oxidation of low-density lipoprotein (LDL) initiates the

atherosclerotic process in the vessel wall by acting as apotent stimulus for the induction of inflammatory geneproducts in vascular endothelial cells. By activating thenuclear factor B (NFB) transcription factor, oxidized

LDL (oxLDL) stimulates increased expression of cellularadhesion molecules. There are several different types ofadhesion molecules with specific functions in theendothelialleukocyte interaction: The selectins tether

and trap monocytes and other leukocytes. Importantly,vascular cell adhesion molecules (VCAMs) andintercellular adhesion molecules (ICAMs) mediate firmattachment of these leukocytes to the endothelial layer.


60/84

OxLDL also augments expression of monocyte

chemoattractant protein 1 (MCP-1) and macrophage-colony stimulating factor (M-CSF). MCP-1 mediatesthe attraction of monocytes and leukocytes and theirdiapedesis through the endothelium into the intima.M-CSF plays an important role in the transformation ofmonocytes to macrophage foam cells. Macrophagesexpress scavenger receptors and take up and

internalize oxLDL in their transformation into foamcells. Migration of smooth muscle cells (SMCs) fromthe intima into the media is another early eventinitiating a sequence that leads to formation of a

fibrous atheroma.


61/84

Primary Pro-inflamatory Cytokines(eg, IL-1, TNF-a)

IL-6Messenger

CytokineICAM-1

Selectins, HSPs, etc.

Proinflammatory RiskFactors

Endotheliumand other cells

CRPSAA

Circulation

Adapted from Libby and Ridker. Circulation. 1999;100:1148-1150.

HSPs=heat shock proteins; SAA=serum amyloid-A.

Liver


62/84


63/84

Total cholesterol: 6mmol/L)


64/84


65/84

LDL-C = (Past) < 130 mg/dl (2001 < 100)

LDL-C=total cholesterol - (HDL-C + .2TG)

HDL-C = (Past) >35 mg/dl (2001) > 40)

HDL-C = > 60 mg/dl will negate one risk factor


66/84

Normal TG = < 200 mg/dl

Borderline high = 200-400 mg/dl

High = 400-1000 mg/dl

Very High = > 1000 mg/dl

Life style is a Driver of CVD


67/84

Chronicheart failure

ArrhythmiaArterial & venous

thrombosis/cardiac & cerebral events

AtherosclerosisAtherosclerosis

HypertensionDiabetes

Dyslipidaemia

Obesity

StressSmoking

Physicalinactivity

Excessivefood intakeLife style intervention

Risk factormodification

Life style is a Driver of CVD


68/84


69/84

At least 3 of

Abdominal obesity: waist circumference > 102 cm (M)

> 88 cm (F)

Hypertriglyceridemia > 150 mg/dl

Low HDL cholesterol < 40 mg/dl (M)

< 50 mg/dl (F)

Hypertension (> 130/85 mm Hg)

Impaired Fasting Glucose or Type 2 diabetes (> 100

mg/dl)

(ATP III. JAMA 285:2486, 2001)


70/84

Type 2 Diabetes

Hypertension

DyslipidemiaCentral obesity

Insulin

Resistance

Pathophysiology of the metabolic syndrome leading


71/84

Reilly & Rader 2003;

Eckel et al 2005

Plaque rupture/thrombosis

Cardiovascular events

Atherosclerosis

Insulin resistance

Tg Metabolic syndrome HDL BP

Inflammatory markers

p y gy y gto atherosclerotic CV disease

Adipocyte Monocyte/

macrophag

Genetic variationEnvironmental factors

Abdominal obesity

CytokinesAdipokines


72/84

Treatment NCEP ATP-III guidelines

Modification of lipids and major risk factors

See Table 15.9

Medications

See Table 15.10

Procedures

Angioplasty

CABG


73/84


74/84


75/84


76/84

Nicotinic Acid (Niaspan)

Bile Acid Sequestrants (cholestyramine andcolestipol)

HMG CoA Reductase Inhibitors (lovastatin,pravastatin, simvastatin)

Fibric Acid Derivatives (Clofibrate, gemfibrozil)

Probucol


77/84


78/84

Nutrition Therapy Therapeutic Lifestyle Changes (TLC) developed

as component of ATP-III

Modifications in fat, cholesterol

Rich in fruits, vegetables, grains, fiber Limit sodium to 2400 mg

Include stanol esters

See the next Table for summary


79/84

Nutrient RecommendedIntake

Saturated fat < 7% of total calories

Polyunsaturated fat Up to 10% of totalcalories

Monounsaturated fat Up to 20% of total

calories Total fat 25-30% of total calories

Carbohydrates 50-60% of total calories

Fiber 20-30 grams/day

Protein Approx. 15% of totalcalories

Limit Cholesterol intake


80/84

Nutrition Therapy - Other Increase sources of soluble fiber

Increase intake of plant sterols

Weight loss BMI 18.5-24.9 Regular physical activity


81/84


82/84

CoronaryAngioplasty

Coronary BypassSurgery (CABG)


83/84

Fish Oil (source of omega-3 polyunsaturated fatty acids) Salmon, flaxseed, canola oil, soybean oil and nuts At high doses > 6 grams/day reduces TG by inhibition of VLDL-TGsynthesis and apolipoprotein B Possibly decreases small LDL (by inhibiting CETP) Several studies have shown lower risk of coronary events 2 servings of fish/week recommended?? Pharmacologic use restricted to refractory hypertriglyceridemia Number of undesirable side effects (mainly GI)

Soy Source of phytoestrogens inhibiting LDL oxidation 25-50 grams/day reduce LDL by 4-8% Effectiveness in postmenopausal women is questionable

Garlic Mixed results of clinical trials In combination with fish oil and large doses (900-7.2 grams/d), decreases

in LDL observed Cholesterol-lowering Margarines

Benecol and Take Control containing plant sterols and stanols Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis 10-20% reduction in LDL and TC however no outcome studies AHA recommends use only in hypercholesterolemia pts or those with a cardiac

event requiring LDL treatment


84/84

Other agents include soluble fiber, nuts (esp. walnuts),green tea

Overall a combination diet with multiple cholesterol-lowering agents causes much more significant LDLreductions

Fiber: Decreases LDL; increases HDL Carrots/Grapefruit: Fiber and pectin (whole fruits most

beneficial) Avocado: monounsaturated fat Beans: High in fiber, low fat; contain lecithin Phytosterols: sesame, safflower, spinach, okra,

strawberries, squash, tomatoes, celery, ginger. Shiitake mushrooms: contain lentinan (25% reduction in

animal studies) Garlic, onion oil: lowers chol. 10-33% Omega 3 fish oils

Documents

Biochemistry Lipoprotein