LIPIDS 101

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LIPIDS 101

• Ulrich K. Schubart
• JMC
• AECOM

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• Physiology of Lipids and Lipoproteins
• Lipoprotein Disorders

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ENERGY STORAGE
ENERGY PRODUCTION
STEROID SYNTHESIS
CELL MEMBRANES
BILE ACIDS
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Polar surface coat
Cholesterol
Non-polar Lipid Core
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COMPOSITION OF PLASMA LIPOPROTEINS
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5
7
6
19
22
18
22
50
40
5
22
33
6
55
86
Chylomicrons VLDL
LDL HDL
Chylomicrons VLDL
LDL
HDL
Density g/ml
0.93 0.93-1.006
1.019-1.063 1.063-1.25
Size (nM) 75-1200 30-60
18-25
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Cholesterol/cholesteryl esters
Phospholipid
Protein
Triglyceride
Bilheimer. Textbook of Internal Medicine.
19892139-44
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Major apolipoproteins and their functions
Apolipoprotein Structural Ligand Cofactor for
Protein for (/-)
apo A-I HDL LCAT () apo B-100
VLDL, IDL, LDL,Lp(a) LDL receptor apo
B-48 Chylomicrons apo C-II LPL
() apo C-III LPL (-) apo E
Chylo remnants, IDL Remnant
receptor in liver apo (a) Plasminogen (-)
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Exogenous Pathway (Chylomicron metabolism)
Chylomicron Remnant Liver
B48
CE
B48
LPL
CE
CE
TG
TG
C-II
Intestines
Remnant Receptor
Fatty acids
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Endogenous Pathway (VLDL metabolism)
Liver
VLDL Remnant LDL
(VLDL/IDL)
B100
B100
B100
CE
Remnant Receptor
LPL
CE
CE
CE
TG
TG
C-II
Fatty acids
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Basic Pathways in LDL Regulation
apo B-100
apo E
VLDL
VLDL PRODUCTION
LIPOLYSIS
apo C
SHUNT PATHWAY
Liver
VLDL Remnant
LDL CLEARANCE
CONVERSION
Other sites
LDL
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Rader et al JCI 2003
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Nabel E NEJM 2003
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Familial Hypercholesterolemia

• Autosomal Dominant Inheritance
• LDL Receptor Deficiency
• - Heterozygous (1/500)
• - Homozygous (1/1,000,000)
• LDL Cholesterol Increased
• - Heterozygous 2 times (gt250 mg/dl)
• - Homozygous 4-6 times elevated
• Familial Defective apoB is an exact phenocopy
  (note this is NOT Familial Combined HLD)

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Familial Hypercholesterolemia
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Familial Hypercholesterolemia Clinical
Manifestations

• Severe Hypercholesterolemia (LDLgt250 mg/dl)
• - Atherosclerotic vascular disease
• Premature CHD
• Xanthelasma/ Corneal Arcus as young adults
• Tendon Xanthomas
• Arthritic type pains in joints
• Family History of premature CHD

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Familial Hypercholesterolemia Ligand Defective
ApoB
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Familial Combined Hyperlipidemia

• Common (1/100)
• Autosomal dominant pattern of inheritance
• Variable lipoprotein pattern in individual and
  family
• Multiple Phenotypes (IIa, IIb, IV, V)
• Pathophysiology overproduction of apoB-100
  particles
• CHD risk is increased

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Familial Combined Hyperlipidemia (HyperapoB)
Liver
LPL
B100
CE
CE
C-II
Fatty acids
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Familial (Type I) Hyperlipoproteinemia/Chylomicron
emia

• Rare (1/1,000,000)
• Recessive inheritance
• Triglycerides gt 1000 mg/dl with usual diet
• Presents in childhood, especially puberty in
  girls
• Pathophysiology absence of lipoprotein lipase or
  apo C-II
• Complications pancreatitis, xanthomatosis,
  hepatosplenomegaly

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Familial (Type I) Hyperlipoproteinemia/Chylomicron
emia
Chylo/VLDL Remnants LDL
(VLDL/IDL)
Liver
apoB
apoB
B100
LPL
CE
CE
CE
TG
C-II
Fatty acids
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Remnant Removal Disease

• Synonyms Familial Dysbetalipoproteinemia, Type
  III hyperlipoproteinemia, Broad beta disease
• Uncommon 1/1000 1/5000
• Requires apo E2/E2 (1/100) second defect for
  clinical expression
• Pathophysiology impaired clearance of apoB/E
  remnant particles by the remnant receptor
• Chylomicron and VLDL (?-VLDL) remnants accumulate
• Diagnosis VLDL-C/TG gt0.3 broad ?-band on EP
• CHD and peripheral vascular disease
• Palmar and tuberoeruptive xanthomata

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Remnant Removal Disease (Type III Hyperlipidemia)
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Nabel E NEJM 2003
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Primary Hypercholesterolemia Clinical
Classification

• Elevated LDL cholesterol (gt160 mg/dl 1/4 of all
  American Adults)
• - Familial Hypercholesterolemia (1/500)
• - Familial Combined Hyperlipidemia (1/100)
• - Polygenic Hypercholesterolemia (1/4)

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Dietary Hyperlipidemia
apoB-100
VLDL
Apo E
Caloric intake
Overproduction of VLDL TG
Apo C
X
X
Reduced activity of LDL receptors ( Saturated
fat and cholesterol In the diet)
LDL
LDL
Increased conversion to LDL
Other sites
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HDL
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Reverse cholesterol transport
Mature HDL
Bile
Macrophage
Nascent HDL
A-I
A-I
FC
CE
LCAT
FC
CE
ABCA1
Liver
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Reverse cholesterol transport Role of CETP in
HDL Metabolism
Mature HDL
Bile
Macrophage
Nascent HDL
A-I
A-I
FC
CE
CE
LCAT
FC
FC
CE
ABCA1
SR-BI
SRA
CETP
Liver
CE
LDLR
Oxidation
TG
CE
B
VLDL/LDL
CETP cholesteryl ester transfer protein
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Rader D JCI Dec 06
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Rader D JCI Dec 06
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Rader D JCI Dec 06
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Primary (Genetic) Causes of Low HDL-C

• ApoA-I
• Complete apoA-I deficiency
• ApoA-I mutations (eg, ApoA-IMilano)
• LCAT
• Complete LCAT deficiency
• Partial LCAT deficiency (fish-eye disease)
• ABCA1
• Tangier disease
• Homozygous
• Heterozygous
• Familial hypoalphalipoproteinemia (some families)
• Unknown genetic etiology
• Familial hypoalphalipoproteinemia (most families)
  
• Familial combined hyperlipidemia with low HDL-C
• Metabolic syndrome

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Tangier Disease

• Autosomal codominant disorder due to mutations in
  both alleles of ABCA1 gene
• Extremely marked reduction in HDL-C and apoA-I
• Markedly accelerated catabolism of apoA-I and
  apoA-II
• Cholesterol accumulation
• Enlarged orange tonsils
• Hepatosplenomegaly
• Peripheral neuropathy

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Tangier Disease(Continued)

• Increased risk of premature atherosclerotic
  vascular disease
• Pathologic accumulation of cholesterol in
  macrophages and other cells of reticulo-endothelia
  l system (orange tonsils)
• Heterozygotes have moderately reduced HDL-C and
  apoA-I levels and increased risk of premature
  atherosclerotic vascular disease, but no
  tonsillar enlargement or hepatosplenomegaly

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HDL Metabolism in Tangier Disease
Nascent HDL
A-I
A-I
CE
LCAT
FC
FC
ABCA1
Macrophage
Rapid catabolism
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Familial Hypoalphalipoproteinemia

• Dominant disorder due to mutations in one allele
  of ABCA1 gene in some families, and of unknown
  genetic etiology in other families
• Moderate reduction in HDL-C and apoA-I
• Increased risk of premature atherosclerotic
  vascular disease

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Secondary Causes of Low HDL-C

• Smoking
• Obesity (visceral fat)
• Sedentary Lifestyle
• High carbohydrate or very-low-fat diet
• Hypertriglyceridemia (from any cause)
• Drugs
• Beta-blockers
• Androgenic steroids
• Androgenic progestins

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Cholesterol disorders associated with premature
CAD Familial Hypercholesterolemia Low
HDL Nephrotic Syndrome Lp(a) not
ApoA. Triglyceride Disorders associated with
premature CAD () premature CAD (-) premature
CAD Familial Combined HLD Familial
HTG Remnant Removal Dz Familial
Chylomicronemia Central Obesity (metabolic
syndrome) Estrogen Diabetes Alcohol Nephrotic
syndrome/Uremia/dialysis Bile Acid
Resins Hypothyroidism High Carbohydrate
diet Cushings syndrome
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New Concepts in Atherosclerosis Risk
Triglycerides, Small Dense LDL and the Metabolic
Syndrome
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Atherogenic Dyslipidemia
HDL
Metabolic Syndrome
Procoagulant State
Insulin Resistance
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TG
HDL
VLDL IDL

Cigarette Smoking
LDL
Diabetes
Atherosclerosis
CHD
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Metabolic Consequences of Hypertriglyceridemia
Small, dense LDL
Chylomicron remnants
HYPERTRIGLYCERIDEMIA
VLDL remnants
HDL
IDL
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Insulin Resistance and Dyslipidemia
Fat Cells
Liver
FFA
CE
(CETP)
TG
IR
Apo A-I
(CETP)
CE
TG
Kidney
LDL
(lipoprotein or hepatic lipase)
Insulin
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Significance of Small, Dense LDL

• Low cholesterol content of LDL particles
• ? particle number for given LDL-C level
• Associated with ? levels of TG variable LDL-C,
  and ? levels of HDL2
• Marker for common genetic trait associated with
  ? risk of coronary disease (LDL subclass pattern
  B)
• Possible mechanisms of ? atherogenicity
• greater arterial uptake
• ? uptake by macrophages
• ? oxidation susceptibility

Feingold KR et al. Arterioscler Thromb.
1992121496-1502. Lamarche B et al. Circulation.
19979569-75.
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Atherogenic Particles
E
E
B
B
B
Small VLDL Remnant
LDL
IDL
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Atherogenic Cholesterol
VLDL IDL LDL
Total Cholesterol - HDL non HDL cholesterol
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Calculating LDL Cholesterol

• LDL-C TC HDLC TG/5
• Invalid when TG gt 400 mg/dl
• Underestimates atherogenic cholesterol
• when TG gt200 mg/dl
• nonHDL-C TC - HDLC

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Non-HDL Cholesterol

• Predictive of CV Events Rates in Prospective
• Clinical Trials
• Useful when triglycerides gt 200 mg/dl
• Allows use of NCEP LDL guidelines
• ( 30 mg/dl)
• Flexible - Allows use of non fasting samples
• to assess lipid treatment goals

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ATP III The Metabolic Syndrome
Risk Factor Defining Level
Abdominal obesity (Waist circumference)
MenWomen gt102 cm (gt40 in)gt88 cm (gt35 in)
TG ?150 mg/dL
HDL-C
MenWomen lt40 mg/dLlt50 mg/dL
Blood pressure ?130/?85 mm Hg
Fasting glucose ?110 mg/dL
Diagnosis is established when ?3 of these risk
factors are present. Abdominal obesity is more
highly correlated with metabolic risk factors
than is ?BMI. Some men develop
metabolic risk factors when circumference is only
marginally increased.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
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ATP III New Features of GuidelinesFocus on
Multiple Risk Factors

• Persons with diabetes without CHD raised to level
  of CHD risk equivalent
• Framingham 10-year absolute CHD risk projections
  used to identify certain patients with ?2 risk
  factors for more intensive treatment
• Persons with multiple metabolic risk factors (the
  metabolic syndrome) identified as candidates for
  intensified therapeutic lifestyle changes (TLC)

Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
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Its 11 PM.do you know what your Cholesterol is?