Transcript Lipid Transport

Lipid Transport
Lipoprotein Structure, Function,
and Metabolism
Clinical Case
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8 y.o. girl
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Admitted for heart/lung transplantation
Medical history
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Xanthomas at 2 yo
MI symptoms at 7 yo
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Coronary artery bypass at 7 yo
8 yo severe angina, second bypass
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TC=1240mg/dl
TG=350mg/dl
Diet & statin & cholestyramine
Mother TC= 355, father TC=310
TC = 1000mg/dl
Transplantation successful
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TC=260mg/dl, xanthomas regressing
Plasma Lipoproteins
Structure
figure 19-1
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LP core
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Triglycerides
Cholesterol esters
LP surface
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Phospholipids
Proteins
cholesterol
Plasma Lipoproteins
Classes & Functions
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Chylomicrons
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Synthesized in small
intestine
Transport dietary lipids
98% lipid, large sized,
lowest density
Apo B-48
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Apo C-II
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Receptor binding
Lipoprotein lipase activator
Apo E
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Remnant receptor binding
Chylomicron Metabolism
figure 19-3
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Nascent chylomicron
(B-48)
Mature chylomicron
(+apo C & apo E)
Lipoprotein lipase
Chylomicron remnant
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Apo C removed
Removed in liver
Plasma Lipoproteins
Classes & Functions
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Very Low Density
Lipoprotein (VLDL)
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Synthesized in liver
Transport endogenous
triglycerides
90% lipid, 10% protein
Apo B-100
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Apo C-II
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Receptor binding
LPL activator
Apo E
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Remnant receptor
Plasma Lipoproteins
Classes & Functions
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Intermediate Density Lipoprotein
(IDL)
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Synthesized from VLDL during VLDL degradation
Triglyceride transport and precurser to LDL
Apo B-100
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Apo C-II
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Receptor binding
LPL activator
Apo E
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Receptor binding
Plasma Lipoproteins
Classes & Functions
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Low Density
Lipoprotein (LDL)
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Synthesized from IDL
Cholesterol transport
78% lipid, 58%
cholesterol & CE
Apo B-100
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Receptor binding
VLDL Metabolism
figure 19-4
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Nascent VLDL (B-100) + HDL (apo C & E) = VLDL
LPL hydrolyzes TG forming IDL
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75% of IDL removed by liver
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IDL loses apo C-II (reduces affinity for LPL)
Apo E and Apo B mediated receptors
25% of IDL converted to LDL by hepatic lipase
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Loses apo E to HDL
Plasma Lipoproteins
Classes & Functions
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High Density Lipoprotein
(HDL)
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Synthesized in liver and intestine
Reservoir of apoproteins
Reverse cholesterol transport
52% protein, 48% lipid, 35% C &
CE
Apo A
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Apo C
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Activates lecithin-cholesterol
acyltransferase (LCAT)
Activates LPL
Apo E
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Remnant receptor binding
LDL Metabolism
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LDL receptor-mediated
endocytosis
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LDL receptors on ‘coated
pits’
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Endocytosis
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Clathrin: a protein polymer
that stabilizes pit
Loss of clathrin coating
uncoupling of receptor,
returns to surface
Fusing of endosome with
lysosome
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Frees cholesterol & amino
acids
Coordinate Control of Cholesterol
Uptake and Synthesis
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Increased uptake of LDLcholesterol results in:
inhibition of HMG-CoA reductase
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stimulation of acyl CoA:cholesterol acyl
transferase (ACAT)
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reduced cholesterol synthesis
increased cholesterol storage
TG + C -> DG + CE
decreased synthesis of LDL-receptors
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“down-regulation”
decreased LDL uptake
Heterogeneity of LDL-particles
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Not all LDL-particles the same
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Small dense LDL (diameter <256A)
Large buoyant LDL (diameter >256 A)
Lamarche B, St-Pierre AC, Ruel IL, et al. A prospective,
population-based study of low density lipoprotein particle
size as a risk factor for Can J Cardiol 2001;17:859-65.
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2057 men with hi LDL, 5 year follow-up
Those with elevated small dense LDL had RR of 2.2 for IHD
compared to men with elevated large buoyant LDL
Detection expensive
Treatment for lowering small dense LDL similar to lowering
all LDL (diet, exercise, drugs)
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Some drugs (niacin, fibrates) may be more effective at lowering
small dense LDL.
LDL Particle Size and Apolipoprotein B Predict Ischemic
Heart Disease: Quebec Cardiovascular Study
6
6.2
5
(p<0.001)
4
3
2.0
2
1
0
Apo B
1.0
>25.64
1.0
<25.64
LDL Peak Particle Diameter
Lamarche B et al. Circulation(nm)
1997;95:69-75.
>120
mg/dl
<120
mg/dl
HDL Metabolism: Functions
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Apoprotein exchange
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provides apo C and apo E to/from
VLDL and chylomicrons
Reverse cholesterol transport
Reverse cholesterol transport
figure 19-6
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Uptake of cholesterol
from peripheral tissues
(binding by apo-A-I)
Esterification of HDL-C by
LCAT
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LCAT activated by apoA1
Transfer of CE to
lipoprotein remnants
(IDL and CR) by CETP
removal of CE-rich
remnants by liver,
converted to bile acids
and excreted
Resolution of Clinical Case
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Familial hypercholesterolemia (FH)
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Family history
Early xanthomas and very high TC
Absence of LDL-receptors
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Parent TC consistent with heterozygous FH
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Homozygous FH
1/500 Americans with heterozygous FH, treatable with
diet/drugs
1/106 with homozygous FH
Diet and drugs relatively ineffective
Liver has ~70% of LDL-receptors
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Combined liver/heart recommended because of advance
CHD
Exam 2
Monday, July 18
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Lipid Transport
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Chapter 19
MAAG chapter 54
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Type 2 Diabetes and Insulin Resistance in Adipose
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Cholesterol Metabolism
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Effect on LPL causing hyperlipidemia
Signaling fault resulting in inappropriate lipolysis
Chapter 21
MAAG chapter 32
Format
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Multiple choice questions
Short essay questions