Blok 10 Lipoprotein & Dyslipidemia

7/28/2019 Blok 10 Lipoprotein & Dyslipidemia

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BIOCHEMISTRYLIPOPROTEIN & DYSLIPIDEMIA

BY

Dr.Liniyanti D.Oswari, MNS, MSc.


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Learning Objectives

To understand the lipid & lipoprotein metabolismin the body.

Recognize the significance of dyslipidemia in

Atherosclerosis on CVD & CHD, including the roleof HDL-C as a protective risk factor for CVD &CHD

Recognize the relationship dyslipidemia withcentral obesity & Insulin resistance

Examine recent clinical trials of dyslipidemia as itrelates to the prevention and treatment of CVD &CHD


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Lipoproteins

Clusters of lipids associated with proteins thatserve as transport vehicles for lipids in the

lymph and blood


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Lipoproteins

Chylomicrons

VLDL Very low density lipoprotein

IDL Intermediate density lipoprotein

LDL Low density lipoprotein

HDL High density lipoprotein


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Distinguished by sizeand density

Each contains differentkinds and amounts oflipids and proteins

The more lipid, the lower

the density The more protein, the

higher the density

Lipoproteins


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LipoproteinsClass Size (nm) Lipids MajorApoproteins

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


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Lipids (%) in Plasma LipoproteinsLipid Chylomicron VLDL IDL LDL HDL

Cholesterol 9 22 35 47 19

Triglyceride 82 52 20 9 3

Phospholipid 7 18 20 23 28


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The Origins & Major Functions ofLipoproteins


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Functions of Chylomicrons Made by intestinal cells

Most of lipid is triglyceride

Little protein

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

Deliver fatty acids via lipoprotein lipase


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Chylomicron remnants Lipoprotein particle that remains after a

chylomicron has lost most of its fatty

acids Taken up by liver

Contents reused or recycled


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Further Delivery of Lipids in Body Liver

Synthesizes & metabolizes lipids

Central command center for relation oflipid metabolism

Makes additional lipoproteins


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Exogenous Pathway of Lipid Metabolism

Vessel wallCholestAA

FA

P,

glycerol


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Endogenous Pathway of Lipid Metabolism


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Liver

Endogenous & Exogenous Sources of Cholesterol

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)


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Endogenous & Exogenous Cholesterol

Cholesterol is obtained from endogenous and exogenous sources.Endogenous cholesterol is synthesized in all tissues, but primarily theliver, intestine, adrenal cortex, and reproductive tissues, including theplacenta. Exogenous cholesterol is absorbed by the intestine from

dietary and biliary sources and transported to the liver.

1,2

In individualseating a relatively low-cholesterol diet, the liver produces about 800 mgof cholesterol per day to replace bile salts and cholesterol lost in thefeces.2 Depending on diet, people typically consume 300 to 700 mg ofcholesterol daily.3,4 Approximately 1000 mg of cholesterol is secretedby the liver into the bile. Thus, approximately 1300 to 1700 mg of

cholesterol per day passes through the intestines,4 of which about 700mg per day is absorbed.5 Because plasma cholesterol levels aremaintained within a relatively narrow range in healthy individuals, areduction in the amount of dietary cholesterol leads to increasedsynthesis in the liver and intestine.2


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Cholesterol Absorption in the Intestine

1000 mg

Resins

Plant stanols NPC1L1(Ezetimibe)

Inhibitors


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There are several steps involved inthe absorption of cholesterol from

the intestinal lumen. Cholesterol that is absorbed from the intestinal lumen

comes from two sources: dietary cholesterol and biliarycholesterol (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.


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Very-Low-Density Lipoproteins

(VLDL) 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


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VLDL life cycle

1- Assembly andsecretion

2- Hydrolysis by LPL

3- Direct uptake byhepatocyte

4- Flux of pathway into

LDL

3

1

2

4


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Intermediate-Density

Lipoproteins (IDL) Lipoprotein that results from loss of fatty

acids from VLDL

Major lipid is cholesterol esters Proteins similar to VLDL but greater

percentage (15%)

ApoB-100, ApoC, ApoE

Taken up by liver or remain in circulation

Converted to low-density lipoproteins (LDL)


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Low-Density Lipoproteins (LDL) 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


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Effect of Diet on LDL Concentrations

Increase LDL

SFAs

Transfatty acids High cholesterol

intake

Lifestyle factors

Genetics

Decrease LDL

High PUFA diet

-3 fatty acids Dietary fiber

Lifestyle factors

Genetics


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LDL Oxidation and Atherosclerosis


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Mechanism of Atherogenic Dyslipidemia

Insulin resistanceincreased NEFA andglucose flux to liver

Insulin resistanceand decreasedapo-Bdegradation

InsulinresistanceanddecreasedLPL

IR impairs

LDLR

IncreasedVLDL

FCHL

DM II

Metabolicsyndrome


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Increased Atherogenicity of SmallDense LDL

Direct Association Longer residence time in

plasma than normal sized LDLdue to decreased recognitionby receptors in liver

Enhanced interaction withscavenger receptor promotingfoam cell formation

More susceptible to oxidationdue to decreased antioxidantsin the core

Enter and attach more easilyto arterial wall

Endothelial cell dysfunction

IndirectAssociation

Inverse relationship

with HDL Marker for

atherogenic TGremnant accumulation

Insulin resistance


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High-Density Lipoproteins (HDL) Good cholesterol; major lipid is phospholipid Lipoprotein made by liver that circulates in 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


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HDL Metabolism

K E d C f t i Li id


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Key Enzymes and Cofactors in LipidMetabolism

HMG-CoA reductase-reduces HMG-CoA to mevalonic acid inthe rate-limiting step of cholesterol biosynthesis (mainly liverand intestine)

Lipoprotein Lipase- digests TG core of CMC and VLDL

Hepatic Lipase-conversion of IDL to LDL CETP-transfers cholesteryl esters from HDL to other

lipoproteins 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 and VLDL foractivation of LPL and receptor recognition respectively


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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


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Effects of Diet on HDL Concentration

What raises HDL?

Uncertain if low carbohydrate diets offerprotection

High MUFA intake

Lifestyle factors ( Exercise)

Genetic factors influence HDL


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High Density Lipoprotein & Atherosclerosis

Reverse cholesterol transport

Maintenance of endothelial function

Protection against thrombosis WithApo A-I inhibits generation of calcium-

induced procoagulant activity on erythrocytes bystabilizing cell membrane

Low blood viscosity via permitting red cell

deformability

Anti-oxidant properties-may be related to enzymescalled paraoxonase


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Dyslipidemia Characteristics

Elevated triglycerides

Post-prandial lipemia

Small dense LDL (type B)

Elevated LDL

Low HDL cholesterol

Elevated Total Cholesterol

Nature Medicine 2002


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Mechanisms Relating InsulinResistance and Dyslipidemia

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)


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Dyslipidemia in DiabetesIncreased

Apo B

Triglycerides

VLDL

LDL andSmall DenseLDL

Decreased

HDL

Apo A-I


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Insulin Resistance: Associated

Conditions


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Small dense LDL

VLDL1 gives rise tosmall dense LDL

Increase TG/Chol

content through CETP Increase delipidation

by hepatic lipase


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Low HDL-cholesterol HDL-3, larger with apo A,

C-II, & C-III

HDL-2, largest, withadditional apo E.

Best negative correlateCAD

Other functions attributedto HDL: inhibits monocyte

chemotaxis, LDLoxidation

Tulenko 2002 J Nuclear Cardiology 9:638


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Low HDL-cholesterol


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Low HDL-cholesterol

CETP

inhibitors

Low HDL-cholesterol

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


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High triglycerides

Post-prandiallipemia

Small dense LDL(type B)

Low HDL cholesterol

ABCA-1

CETP

Niacin

Statin

Fibrate


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Current Classifications Familial Hypercholesterolemia High LDL-C

(Type IIA)

Polygenic Familial Hypercholesterolemia Familial Combined Hyperlipidemia High

LDL-C and/or high TG levels

Familial DyslipidemiasHigh TG and lowHDL

Familial Dysbetalipoproteinemia (Type III)


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Tangier Disease Genetic disorder resulting in production

of faulty HDL particles that cannot take

up cholesterol from cells High risk for developing cardiovascular

disease


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

Can see the platelet aggregationin response to the foam cellchemicals and tissue damageThe platelets will activate the

coagulation cascade, resulting inthe production of fibrin strandswhich trap platelets, red and whiteblood cells over the area =thrombus

In larger vessels, it takes longer todevelop a thrombus big enough tocompletely block the vessel soyou get warning signs (TIA, UA) ofstroke and MI

This process happenseverywhere (brain, heart)


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Image courtesy of the Internet

Stroke Center at WashingtonUniversity - www.strokecenter.org


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Cardiovascular disease (CVD) General term for all diseases of the

heart and blood vessels

Atherosclerosis is the main cause of CVDAtherosclerosis leads to blockage of

blood supply to the heart, damageoccurs (coronary heart disease, CHD) Cardio = heart

Vascular = blood vessels

Coronary Heart Disease [CHD]


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MVS 110: Lecture#11

Coronary Heart Disease [CHD]Athrogenesis


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Lipoproteins and cardiovascular

disease (CVD) risk LDL is positively associated with CVD

HDL is negatively associated with CVD


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A Plethora of Non-Lipid Markers of Risk

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

2. Atherosclerosis Burden/End-organ Damage:Carotid IMT, # plaques (based on carotidUS), IVUS, EBCT, advanced CT, MRI

3. General Inflammatory Marker:

hs-C Reactive Protein

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

5. Other: Homocysteine

Ath l i I I fl t Di


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Atherosclerosis Is an Inflammatory Disease

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

A h l i I I fl Di


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Atherosclerosis Is an Inflammatory DiseaseOxidation of low-density lipoprotein (LDL) initiates the

atherosclerotic process in the vessel wall by acting asa potent stimulus for the induction of inflammatorygene products in vascular endothelial cells. Byactivating the nuclear factor B (NFB) transcription

factor, oxidized LDL (oxLDL) stimulates increasedexpression of cellular adhesion molecules. There areseveral different types of adhesion molecules withspecific functions in the endothelialleukocyte

interaction: The selectins tether and trap monocytesand other leukocytes. Importantly, vascular celladhesion molecules (VCAMs) and intercellularadhesion molecules (ICAMs) mediate firm attachment

of these leukocytes to the endothelial layer.

A h l i I I fl Di


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Atherosclerosis Is an Inflammatory Disease

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.

The Acute Phase Response Pathway


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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.

The Acute-Phase Response Pathway

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

Liver

LDL and atherosclerosis


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LDL and atherosclerosis


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Recommended blood lipids

Total cholesterol:


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Desirable Blood Cholesterol

Normal = < 200 mg/dl (5.2 mmol/L)

Borderline = 200-239 mg/dl or (5.2-

6mmol/L) Hypercholesterolemia > 240 mg/dl or >

6mmol/L)


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Desirable Levels LDL & HDL Continued

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

Desirable Levels Triglyceride


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Desirable Levels TriglycerideContinued

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


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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

D fi i i (NCEP)


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Definition:(NCEP)National Cholesterol Education Program (2001)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)

Pathogenesis of the Metabolic


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Pathogenesis of the MetabolicSyndrome

Type 2 Diabetes

Hypertension

DyslipidemiaCentral obesity

Insulin

Resistanc

e

Pathophysiology of the metabolic syndrome leading


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Reilly & Rader 2003;

Eckel et al 2005

Plaque rupture/thrombosis

Cardiovascular events

Atherosclerosis

Insulin resistance

Tg Metabolic syndrome HDL BP

Inflammatory markers

Pathophysiology of the metabolic syndrome leadingto atherosclerotic CV disease

Adipocyte Monocyte/

macrophag

Genetic variationEnvironmental factors

Abdominal obesity

CytokinesAdipokines


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Treatment Treatment

NCEP ATP-III guidelines

Modification of lipids and major risk factors

See Table 15.9

Medications

See Table 15.10

ProceduresAngioplasty

CABG


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Drugs

Nicotinic Acid (Niaspan)

Bile Acid Sequestrants (cholestyramine and

colestipol) HMG CoA Reductase Inhibitors (lovastatin,

pravastatin, simvastatin)

Fibric Acid Derivatives (Clofibrate,gemfibrozil)

Probucol


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Treatment 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 Table 15.11 for summary, completeguidelines in Appendix E9

Nutrient Recommendations of TLC Diet


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(TLC= Therapeutic lifestyle Changes)Nutrient Recommended

Intake Saturated fat < 7% of total calories

Polyunsaturated fat Up to 10% of total calories

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 total calories

Limit Cholesterol intake


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Nutrition Therapy - Other

Increase sources of soluble fiber

Increase intake of plant sterols

Weight loss BMI 18.5-24.9

Regular physical activity


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Medical Treatments

CoronaryAngioplasty

Coronary BypassSurgery (CABG)

Diet Supplements


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pp 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-TG synthesis 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 Other agents include soluble fiber, nuts (esp. walnuts), green tea Overall a combination diet with multiple cholesterol-lowering agents causes much more

significant LDL reductions

Cholesterol Control With Foods


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Cholesterol Control With Foodsand Herbs

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 Red Yeast Rice: a natural substance that inhibits

HMG C A d S i di i L i

Documents

Blok 10 Lipoprotein & Dyslipidemia