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Your Cholesterol Your Cholesterol ProfileProfile
Gary E. Foresman, MDGary E. Foresman, MD
February, 2011February, 2011
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Cholesterol MetabolismCholesterol Metabolism1.1. Cholesterol is an alicyclic compound with a Cholesterol is an alicyclic compound with a
structure:structure:
a.a. Perhydrocyclopentanophenanthrene Perhydrocyclopentanophenanthrene nucleus of 4 fused rings nucleus of 4 fused rings (5-cholesten-3B-01)(5-cholesten-3B-01)
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Cholesterol MetabolismCholesterol Metabolism
2.2. Low solubility in water: 0.2mg / 100ml at Low solubility in water: 0.2mg / 100ml at 250 C250 C
3.3. Solubility in blood is due to lipoproteins Solubility in blood is due to lipoproteins (LDL, VLDL)(LDL, VLDL)
4.4. Total cholesterolTotal cholesterol
a.a. Free 30%Free 30%
b.b. Cholesterol Esters 70% (FA is Saturated or Cholesterol Esters 70% (FA is Saturated or Unsaturated)Unsaturated)
Long chain FA attached by ester bond to Long chain FA attached by ester bond to OH group on C-3 on the A-ring (usually OH group on C-3 on the A-ring (usually linoleic acid) enhances hydrophobiticity.linoleic acid) enhances hydrophobiticity.
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Cholesterol MetabolismCholesterol Metabolism
5. Structure:
6. Bile concentration = 390 mg %
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7. Cholesterol Functions:A. Plasma and intracellular membranes (Free
Unesterified form)B. Myelinated structures of brain and CNSC. Inner Mitrochrondrial MembraneD. Bile AcidsE. Steroid Hormones and Sex HormonesF. Ergosterol ----- UV Skin --> Vitamin D3
(cholecalciferol)
8. Synthesis is greatest in:– Liver– Intestine– Adrenal Cortex– Reproductive Tissues (Ovary, Testes)
Cholesterol MetabolismCholesterol Metabolism
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1. Also called mevalonate: NADP+ oxidoreductase (a residentglycoprotein).
2. Requires NADPH as reductant -2 moles (4 E-)3. Hydrolysis of thioester bond of HMG-CoA4. Generates a primary alcohol residue : mevalonate5. Irreversible RX6. Produces (R) – (+) mevalonate with 6 C atoms7. Rate limiting step8. Intrinsic membrane protein of the ER (Endoplasmic
Reticulum) whose carboxyl terminus extends into the cytosol and carries the enzyme’s active site. N-terminus anchors it to ER.
9. Phosphorylation regulates activity by AMP activated protein kinasethat diminishes its catalytic activity
HMG-CoA Reductase HMG-CoA Reductase EnzymeEnzyme
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10. Increased intracellular cholesterol stimulates the phosphorylation ofHMGCoA Reductase
11. Most regulated enzyme known in humans: • Concentrations of products of mevalonate pathway
• Cholesterol• Farnesyl Pyrophosphate (FPP)
• Prenylated proteins• 2-cis geranylgeranyl PP (GGPP) Dolichols• All-trans geranylgeranyl (GGPP) Ubiquinone
• Heme• Selenoproteins
HMG-CoA Reductase HMG-CoA Reductase EnzymeEnzyme
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The New Gold Standard for Lipoprotein Analysis
Ad
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Testi
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for
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“The Lipid Panel”
Evolution of Lipoprotein Evolution of Lipoprotein TestingTesting
Direct LDL is Better
Total Cholesterol =Total Cholesterol = VLDLVLDL + + LDL LDL + +
HDLHDL
Calculated LDL = TC – (HDL + TG/5)
Friedewald Equation: VLDL = TG/5
Lipoprotein Particle Numbers by Subgroup is Best
Apo B 100 (est. of non-HDL Particles) is Better Yet
Consensus Statement of the American Diabetes Assoc. & American College of Cardiology
Lipoprotein Particles Predict Risk Better than Cholesterol
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Separation by Density Separation by Density
Centrifuge Tube with Mixture of Serum, Gradient and Dye
Proteins
LDL
VLDL
HDL
Intense Gravitational Force
Separated Lipoproteins
600,000 G’s
Density (g/ml)
1.030
1.006
1.300
1.000
1.100
1.063
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NCEP Guidelines for Cardiovascular NCEP Guidelines for Cardiovascular Disease Disease
NCEP Identified a Number of New Lipoprotein Risk Factors – To Help Assess Those at Risk
NCEP - ATP III
50% of at Risk Individuals are Not Identified
50% of Heart Attack Victims have
Normal Cholesterol
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NCEP New Lipoprotein Risk NCEP New Lipoprotein Risk FactorsFactors
Small Dense LDL – - 3-fold Greater Risk of CVD than Buoyant LDL - Penetrates Arterial Endothelial Lining Easily - Less Recognized by LDL Receptors therefore Increases
HDL 2b & 3 –- HDL 3 Picks Up Excess Cholesterol and Becomes HDL 2b in Reverse Cholesterol Transport
Lp(a) -- Small Particles that are Easily Oxidized - Competes with Plasminogen, Prevents Fibrinolysis
RLP (Remnant Lipoprotein) - - One of the Most Atherogenic Lipoproteins - Skips Oxidation Step in Forming Plaque
High in 20% of population
High in 25% of population
High in 20% of population
Low in 20% of population
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Lp(a) Competes with Plasminogen Lp(a) Competes with Plasminogen and Prevents Fibrinolysisand Prevents Fibrinolysis
Fibrin
Fibrinogen
Blood Clot(MI, Stroke
or DVT)
Fibrinolysis
Plasmin
Plasminogen
Many of the over 40 genetic variations of Lp(a) mimic plasminogen
Lp(a)
Possible Antithrombotic Therapy Indicated
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To Determine the NCEP NewTo Determine the NCEP New Risk Factors Risk Factors Lipoprotein Subgroup Lipoprotein Subgroup Information is Needed:Information is Needed:
Advanced Lipoprotein Advanced Lipoprotein TestingTesting
What are Lipoproteins and their Subgroups?
How do they Cause Cardiovascular Disease?
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Lipoprotein Lipoprotein Particles Particles
ApolipoproteinA-1 (HDL) or B-
100 (LDL)
Unesterified Cholesterol
Cholesterol Ester
Phospholipid
Triglyceride
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Atherogenic Atherogenic ParticlesParticles
Size (nm)Size (nm)
Density (g/ml)Density (g/ml)
VLDLVLDL
1.0041.0045050
TG-rich LipoproteinsTG-rich Lipoproteins
RLPRLP
2525
1.0131.013
BuoyantBuoyant LDLLDL
2222
1.0231.023
DenseDenseLDLLDL
1919
1.0441.044
Mean EndothelialMean EndothelialPore SizePore Size
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CETP in Cholesterol CETP in Cholesterol MetabolismMetabolismHL
LDL 1-2
LPLIDL
HL
LDL 3-4
HDL Enters Cells &
Arterial Intima NascentHDL
Apo A-1
Liver
CETPTG’s
CE
VLDL
Apo B-100
Liver
LCAT
HDL3Reverse
Cholesterol Transport
LCAT
HDL2b
Brewer HB et al. Am J Cardiol 2003;92:10K-16K.
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HDL REMOVESEXCESS LIPIDS
ARTERIAL INTIMA
MACROPHAGE CELL
FOAMCELLSBUILD
PLAQUE
RLP
Atherosclerotic Plaque Atherosclerotic Plaque FormationFormation
ARTERIAL LUMEN
DENSELDL
Lp(a)
INFLAMMATION RUPTURES PLAQUE
LDL
OXIDIZEDLDL
MONOCYTE CELL
FOAM CELL
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Atherogenic Profile
LPP showing NCEP’s New Lipoprotein Risk LPP showing NCEP’s New Lipoprotein Risk FactorsFactors
Atherogenic Profile
High RLP
Dense LDL
Low HDL 2b
Healthy Profile
Buoyant LDL High HDL
2bLow RLP
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of DyslipidemiaTreatment of Dyslipidemia
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Date
March of 2010
Aug. of 2010
Nov. of 2010Feb. of 2011
Total Cholesterol
258 146 167 188
Triglycerides 164 71 73 233
HDL 44 50 66 44
LDL 181 82 86 97
LDL/HDL 4.1 1.4 1.1 2.2
Trig/HDL 3.7 1.6 1.3 5.3
*Add Lipitor 20mg
and 3g/day Arctic PureEPA/DHA
*Patient switches to
Kirkland Fish Oils
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Treatment of Treatment of DyslipidemiaDyslipidemia
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Lipoprotein Therapeutic Statins Niacin Fibrates Estrogens Resins Absorption Omega-3’s Alcohol Life Style Inhibitors EPA & DHA (moderate) Changes (diet & exercise)
VLDL (Triglycerides) ♥ ♥ ♥♥ ♥♥ X X ♥ ♥♥ ■
RLP (IDL) ♥ ♥ ♥ ♥ X X ♥ ♥♥** ■
LDL I & II - buoyant ♥ ♥♥ ♥ ♥ ♥ ♥ ♥ ♥ ** ■
LDL III - dense ♥ ♥** ♥♥ ♥ ♥♥ ♥ ♥ ■ ■
LDL IV or Lp(a) ■ ■ ♥♥ ■ ♥ ■ ■ ■ ■
HDL 2b - buoyant ♥♥ ♥ ♥ ♥ ♥ ■ ■ ■ ♥
HDL 2a & 3 ♥ ♥ ♥♥ ♥ ♥ ■ ■ ■ ♥ _____________________________________________________________________________________________________ _____________
♥♥ Therapeutic ♥ Beneficial ■ Little or No Effect X Negative Result *These guidelines provide some of the treatment options available to modify lipoprotein particle numbers determined by the LPPTM test. **Spectracell Laboratories observed response to treatment. The National Cholesterol Education Program (NCEP) guidelines provide dosage information on the treatment options.
Lipoprotein Particle Lipoprotein Particle Numbers Numbers
Therapeutic GuidelinesTherapeutic Guidelines
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