LIPIDS 101
Ulrich K. Schubart
JMC
AECOM
•Physiology of Lipids and Lipoproteins
• Lipoprotein Disorders
COMPOSITION OF PLASMA LIPOPROTEINS
2
7
5
6
19
18
22
50
40
22
5
22
86
Chylomicrons
Chylomicrons
Density
g/ml
Size (nM)
0.93
75-1200
55
VLDL
VLDL
0.93-1.006
30-60
Cholesterol/cholesteryl esters
Triglyceride
6
LDL
LDL
1.019-1.063
18-25
Phospholipid
Protein
33
HDL
HDL
1.063-1.25
9-12
Exogenous Pathway (Chylomicron metabolism)
Chylomicron
Remnant
Liver
B48
CE
TG
Apo E
LPL
C-II
CE
CE
TG
B48
Apo E
Intestines
Remnant Receptor
Fatty acids
Endogenous Pathway (VLDL metabolism)
Liver
VLDL
B100
Remnant
Receptor
CE
TG
Apo E
Remnant
(VLDL/IDL)
LDL
B100
LPL
C-II
CE
CE
TG
Apo E
Fatty acids
B100
CE
Basic Pathways in LDL Regulation
apo B-100
apo E
VLDL
VLDL
PRODUCTION
LIPOLYSIS
apo C
SHUNT PATHWAY
Liver
VLDL
Remnant
LDL
CLEARANCE
Other sites
CONVERSION
LDL
Rader et al JCI 2003
Nabel E NEJM 2003
Familial Hypercholesterolemia
• Autosomal Dominant Inheritance
• LDL Receptor Deficiency:
-
Heterozygous (1/500)
-
Homozygous (1/1,000,000)
• LDL Cholesterol Increased
-
Heterozygous 2 times (>250 mg/dl)
-
Homozygous 4-6 times elevated
• Familial Defective apoB is an exact phenocopy
(note this is NOT Familial Combined HLD)
Familial Hypercholesterolemia
Liver
ChyloVLDL
Remnants
LDL
apoB
CE
TG
Apo E
LPL
C-II
CE
CE
TG
apoB
Apo E
Fatty acids
B100
LDL-R
Familial Hypercholesterolemia: Clinical
Manifestations
• Severe Hypercholesterolemia (LDL>250 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
Familial Hypercholesterolemia: Ligand
Defective ApoB
Liver
ChyloVLDL
Remnants
LDL
apoB
CE
TG
Apo E
LPL
C-II
CE
CE
TG
apoB
Apo E
Fatty acids
B100
LDL-R
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
Familial Combined Hyperlipidemia
(HyperapoB)
Liver
VLDL
B100
CE
LPL
TG
Apo E
C-II
Remnant
(VLDL/IDL)
CE
CE
TG
B100
Apo E
Fatty acids
LDL
B100
CE
LDL-R
Familial (Type I)
Hyperlipoproteinemia/Chylomicronemia
• Rare (1/1,000,000)
• Recessive inheritance
• Triglycerides > 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
Familial (Type I)
Hyperlipoproteinemia/Chylomicronemia
Liver
Chylo/VLDL
Remnants
(VLDL/IDL)
LDL
apoB
CE
TG
Apo E
LPL
C-II
CE
CE
TG
apoB
Apo E
Fatty acids
B100
CE
LDL-R
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 >0.3; broad -band on EP
_ disease
• CHD and peripheral vascular
• Palmar and tuberoeruptive xanthomata
Remnant Removal Disease
(Type III Hyperlipidemia)
Liver
ChyloVLDL
Remnants
LDL
apoB
CE
TG
Apo E
LPL
C-II
CE
CE
TG
apoB
Apo E2/E2
Fatty acids
B100
LDL-R
Nabel E NEJM 2003
Primary Hypercholesterolemia:
Clinical Classification
• Elevated LDL cholesterol (>160 mg/dl; 1/4 of all
American Adults)
-
Familial Hypercholesterolemia (1/500)
-
Familial Combined Hyperlipidemia (1/100)
-
Polygenic Hypercholesterolemia (1/4)
Dietary Hyperlipidemia
apoB-100
Apo E
Caloric
intake
VLDL
Overproduction of
VLDL TG
Apo C
VLDL
remnants
X
X
Reduced activity
of LDL receptors
( Saturated fat and
cholesterol In the diet)
Other sites
LDL
LDL
Increased conversion
to LDL
HDL
Reverse cholesterol transport
Bile
F
C
Liver
Mature
HDL
A-I
CE
CE
Nascent HDL
A-I
LCAT
Macrophage
FC ABCA1
FC
CE
Reverse cholesterol transport :
Role of CETP in HDL Metabolism
Mature
HDL
A-I
Bile
FC
CE
SR-BI
Liver
Nascent HDL
A-I
LDLR
LCAT
CE
CE
CE
VLDL/LDL
CETP = cholesteryl ester transfer protein
FC ABCA1FC
SRA
CETP
TG
Macrophage
B
CE
Rader D JCI Dec 06
Rader D JCI Dec 06
Rader D JCI Dec 06
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
Cholesterol disorders associated with premature CAD
Familial Hypercholesterolemia
Nephrotic Syndrome
Lp(a) [ not ApoA].
Low HDL
Triglyceride Disorders associated with premature CAD
(+) premature CAD
(-) premature CAD
Familial Combined HLD
Remnant Removal Dz
Central Obesity (metabolic syndrome)
Diabetes
Nephrotic syndrome/Uremia/dialysis
Hypothyroidism
Cushing’s syndrome
Familial HTG
Familial Chylomicronemia
Estrogen
Alcohol
Bile Acid Resins
High Carbohydrate diet
New Concepts in Atherosclerosis
Risk:
Triglycerides, Small Dense LDL
and the Metabolic Syndrome
Atherogenic
Dyslipidemia
HDL
BP
Metabolic
Syndrome
Insulin Resistance
Procoagulant
State
TG
HDL
VLDL
IDL
LDL
Diabetes
Cigarette
Smoking
Hypertension
Atherosclerosis
Thrombosis
Pro Coagulant
State
CHD
Metabolic Consequences
of Hypertriglyceridemia
Chylomicron
remnants
Small, dense
LDL
HYPERTRIGLYCERIDEMIA
HDL
IDL
VLDL
remnants
Insulin Resistance and
Dyslipidemia
Fat Cells
v
IR
Liver
FFA
TG
Apo B
VLDL
CE
VLDL
(CETP)
TG
CE(CETP)TG
HDL
Apo A-I
Kidney
Insulin
SD
LDL (lipoprotein LDL
or
hepatic lipase)
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. 1992;12:1496-1502.
Lamarche B et al. Circulation. 1997;95:69-75.
Atherogenic Particles
E
E
B
B
B
C
Small VLDL
Remnant
IDL
LDL
Atherogenic Cholesterol
VLDL + IDL + LDL
= Total Cholesterol - HDL
= non HDL cholesterol
Calculating LDL Cholesterol
• LDL-C = TC – HDLC – TG/5
• Invalid when TG > 400 mg/dl
• Underestimates “atherogenic cholesterol”
when TG >200 mg/dl
• nonHDL-C = TC - HDLC
Non-HDL Cholesterol
Predictive of CV Events Rates in
Prospective
Clinical Trials
Useful when triglycerides > 200 mg/dl
Allows use of NCEP LDL guidelines
(+ 30 mg/dl)
Flexible - Allows use of non fasting
samples
to assess lipid treatment goals
ATP III: The Metabolic Syndrome*
Risk Factor
Defining Level
Abdominal obesity†
(Waist circumference‡)
Men
>102 cm (>40 in)
Women
>88 cm (>35 in)
TG
150 mg/dL
HDL-C
Men
<40 mg/dL
Women
<50 mg/dL
Blood pressure
130/85 mm Hg
*Diagnosis
is established
when 3 of these risk factors are present.
Fasting
glucose
110 mg/dL
†
Abdominal obesity is more highly correlated with metabolic risk factors than is
‡Some men develop metabolic risk factors when circumference is only
BMI.
marginally
increased.
Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
ATP III: New Features of Guidelines—
Focus 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 of
High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
“It’s 11 PM….do you know what your Cholesterol is?