Blok 10 Lipoprotein & Dyslipidemia
Transcript of 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