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Chylomicrons
VLDL
Distinguished by size
and density
Each contains
different kinds and
amounts of lipids
and proteins
Class
Size (nm)
Lipids
Major
Apoproteins
Chylomicra
100-500
Dietary TG
B-48,C-II,E
VLDL
30-80
Endogenous
TG
B-100,C-II,E
IDL
25-50
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
Chylomicro
n
VLDL
IDL
Cholesterol
22
35
47
19
Triglyceride
82
52
20
Phospholipi
d
18
20
23
28
Lipid
LDL HDL
Chylomicron
remnants
Liver
Synthesizes & metabolizes lipids
Central command center for relation of lipid
metabolism
Makes additional lipoproteins
12
13
Cholest
AA
FA
P,
glycerol
Vessel
wall
Dietary
cholesterol
Exogenous
Intestine
(~300700 mg/day)
Biliary
cholesterol
Fecal bile
acids
and neutral
sterols
~700 mg/day
(~1000 mg/day)
Liver
Synthesis
(~800 mg/day)
Extrahepatic
tissues
Endogenous
Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew
RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777;
Ginsberg HN, Goldberg IJ. In Harrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill,
1998:2138-2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of
Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.
1000 mg
Inhibitors
Resins
Plant stanols
NPC1L1
(Ezetimibe)
Made by liver
Contains large amounts of triglyceride
Delivers fatty acids to cells
More dense than chylomicrons
A bit more protein (8%)
1- Assembly and
secretion
2- Hydrolysis by LPL
3- Direct uptake by
hepatocyte
4- Flux of pathway
into LDL
3
1
2
4
Cell membranes
Hormone production
Protein (21%)
ApoB-100
Binds to specific LDL receptor
LDL receptors
Increase LDL
SFAs
Trans fatty acids
High cholesterol
intake
Lifestyle factors
Genetics
Decrease LDL
Insulin resistance
increased NEFA
and glucose flux to
liver
Increased
VLDL
IR impairs
LDLR
Insulin
resistance and
decreased apoB degradation
Insulin
resistance
and
decreased
LPL
FCHL
DM II
Metabolic
syndrome
Direct
Association
Indirect
Association
Inverse relationship
with HDL
Marker for
atherogenic TG
remnant
accumulation
Insulin resistance
Good
Antiinflammatory
Anti-thrombotic
Modulation of
endothelial function
HDL-C
Cholesterol
acceptor
Cholesterylester
donor
Reverse
Cholesterol
Transport (RCT)
Elevated triglycerides
Post-prandial lipemia
Small dense LDL (type
B)
Elevated LDL
Low HDL cholesterol
Elevated Total
Cholesterol
Fat Cells
Liver
FFA
IR
Insulin
CE
TG
VLDL (CETP) HDL
(hepatic lipase)
Apo B
TG
VLDL
Apo A-1
CE (CETP) TG
LDL
SD
LDL
(lipoprotein
or
hepatic lipase)
Kidney
Increased
Apo B
Triglyceride
s
VLDL
LDL and
Small Dense
LDL
Decreased
HDL
Apo A-I
Low HDL-cholesterol
Increased catabolism of small dense
HDL
Low HDL cholesterol by both content
and # particles
CETP
inhibitors
High triglycerides
Post-prandial
lipemia
Small dense LDL
(type B)
Low HDL
cholesterol
Fibrate
Niacin
Statin
CETP
ABCA-1
Fredrickson-Levy-Lees Classification
Type
Lipoprotein Elevation
Chylomicrons
IIa
LDL
IIb
LDL + VLDL
III
IDL (LDL1)
IV
VLDL
VLDL + Chylomicrons
IDL, intermediate-density lipoprotein
LDL, low-density lipoprotein
VLDL, very-low-density lipoprotein
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th47
Edition: http://www.accesspharmacy.com
Lipid Phenotype
Plasma Lipid
Phenoty
Levels [mmol/L
Lipoprotein pe
(mg/dL)]
Elevated
Isolated hypercholesterolemia
Familial
Heterozygotes TC = LDL
IIa
hypercholesterolem 713 (275500)
ia
Clinical Signs
Homozygotes TC
>13 (>500)
LDL
IIa
Usually develop
xanthomas in adulthood
and vascular disease in
childhood
Familial defective
Apo B-100
Heterozygotes TC = LDL
713 (275500)
IIa
IIa
Usually asymptomatic
until vascular disease
develops; no xanthomas
IV
Asymptomatic; may be
associated with
increased risk of
vascular disease
Polygenic
TC = 6.59 (250
hypercholesterolem 350)
ia
LDL
Isolated hypertriglyceridemia
Familial
TG= 2.88.5 (250 VLDL
hypertriglyceridemi 750)
a
Familial LPL
deficiency
TG>8.5 (750)
Chylomicron I, V
s, VLDL
Usually develop
xanthomas in adulthood
and vascular disease at
3050 years
May be asymptomatic;
may be associated with
pancreatitis, abdominal
pain,
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th
hepatosplenomegaly 48
Edition: http://www.accesspharmacy.com
Lipid
Phenotype
Dysbetalipoproteinemia
VLDL, IDL;
LDL normal
III
Usually
asymptomatic until
vascular disease
develops; familial
form may present as
isolated high TG or
isolated high LDL
cholesterol
Usually
asymptomatic until
vascular disease
develops; may have
palmar or
tuboeruptive
xanthomas
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th49
Edition: http://www.accesspharmacy.com
50 50
Age
Men: 45 years
Women: 55 years or premature menopause without estrogen replacement
therapy
Family history of premature CHD (definite myocardial infarction or sudden
death before age 55 years in father or other male first-degree relative, or
before age 65 years in mother or other female first-degree relative)
Cigarette smoking
Hypertension (140/90 mm Hg or taking antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)b
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th55
Edition: http://www.accesspharmacy.com
Athrogenesis
L-Selectin,
Integrins
VCAMLDLE-Selectin,
1,
P-Selectin
ICAM-1
Monocyt
e
MCP-1
OxLDL
Intima
M-CSF
Other
inflammato
ry triggers
Macrophage
Activation &
Division
Media
Libby et al. Circulation 2002;105:1135-1143.
Proinflammatory
Risk Factors
Primary Pro-inflamatory Cytokines
(eg, IL-1, TNF-)
ICAM-1
Selectins, HSPs,
etc.
Endothelium
and other
cells
IL-6
Messenger
Cytokine
CRP
SAA
Liver
Circulation
HSPs=heat shock proteins; SAA=serum amyloid-A.
Adapted from Libby and Ridker. Circulation. 1999;100:1148-1150.
Total
Normal
Physical
inactivity
Excessive
food intake
Stress
Smoking
Obesity
Hypertension
Risk factor
modificatio
n
Diabetes
Dyslipidaemia
Atherosclerosis
Chronic
heart failure
Atherosclerosis
Arrhythmia
At least 3 of
Abdominal obesity: waist circumference > 102 cm (M)
> 88 cm (F)
Hypertriglyceridemia
Central
obesity
Insulin
Resistanc
e
Type 2
Diabetes
Dyslipidemi
a
Hypertensio
n
Environmental factor
Genetic variation
Abdominal
Adipokines obesity
Adipocyte
Cytokines
Monocyte/
macrophag
Inflammatory markers
Insulin resistance
Tg
Metabolic syndrome
HDL
BP
Atherosclerosis
Plaque rupture/thrombosis
Cardiovascular events
Treatment
NCEP ATP-III guidelines
Modification of lipids and major risk factors
See Table 15.9
Medications
See Table 15.10
Procedures
Angioplasty
CABG
Nutrition Therapy
Therapeutic Lifestyle Changes (TLC) developed
as component of ATP-III
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
<200 mg/day
Total calories
Balance energy intake and
expenditure to maintain
desirable body weight/
prevent weight gain
*Avoid Trans Fats.
*Increase Intake of Omega -3 essential Fatty Acids
*From Journal Of the American Medical Association 285 :248697(2001)
Coronary
Angioplasty
Coronary Bypass
Surgery (CABG)