1. Lipoprotein Structure, Function, and Metabolism
Lipid Transport
Lipoprotein Structure, Function, and Metabolism

2. Clinical Case 8 y.o. girl Medical history Transplantation successful
Admitted for heart/lung transplantation
Medical history
Xanthomas at 2 yo
MI symptoms at 7 yo
TC=1240mg/dl
TG=350mg/dl
Diet & statin & cholestyramine
Mother TC= 355, father TC=310
Coronary artery bypass at 7 yo
8 yo severe angina, second bypass
TC = 1000mg/dl
Transplantation successful
TC=260mg/dl, xanthomas regressing

3. Plasma Lipoproteins Structure figure 19-1
LP core
Triglycerides
Cholesterol esters
LP surface
Phospholipids
Proteins
cholesterol

4. Plasma Lipoproteins Classes & Functions
Chylomicrons
Synthesized in small intestine
Transport dietary lipids
98% lipid, large sized, lowest density
Apo B-48
Receptor binding
Apo C-II
Lipoprotein lipase activator
Apo E
Remnant receptor binding

5. Chylomicron Metabolism figure 19-3
Nascent chylomicron (B-48)
Mature chylomicron (+apo C & apo E)
Lipoprotein lipase
Chylomicron remnant
Apo C removed
Removed in liver

6. Plasma Lipoproteins Classes & Functions
Very Low Density Lipoprotein (VLDL)
Synthesized in liver
Transport endogenous triglycerides
90% lipid, 10% protein
Apo B-100
Receptor binding
Apo C-II
LPL activator
Apo E
Remnant receptor binding

7. Plasma Lipoproteins Classes & Functions
Intermediate Density Lipoprotein (IDL)
Synthesized from VLDL during VLDL degradation
Triglyceride transport and precurser to LDL
Apo B-100
Receptor binding
Apo C-II
LPL activator
Apo E

8. Plasma Lipoproteins Classes & Functions
Low Density Lipoprotein (LDL)
Synthesized from IDL
Cholesterol transport
78% lipid, 58% cholesterol & CE
Apo B-100
Receptor binding

9. VLDL Metabolism figure 19-4
Nascent VLDL (B-100) + HDL (apo C & E) = VLDL
LPL hydrolyzes TG forming IDL
IDL loses apo C-II (reduces affinity for LPL)
75% of IDL removed by liver
Apo E and Apo B mediated receptors
25% of IDL converted to LDL by hepatic lipase
Loses apo E to HDL

10. Plasma Lipoproteins Classes & Functions
High Density Lipoprotein (HDL)
Synthesized in liver and intestine
Reservoir of apoproteins
Reverse cholesterol transport
52% protein, 48% lipid, 35% C & CE
Apo A
Activates lecithin-cholesterol acyltransferase (LCAT)
Apo C
Activates LPL
Apo E
Remnant receptor binding

11. LDL Metabolism LDL receptor-mediated endocytosis
LDL receptors on ‘coated pits’
Clathrin: a protein polymer that stabilizes pit
Endocytosis
Loss of clathrin coating
uncoupling of receptor, returns to surface
Fusing of endosome with lysosome
Frees cholesterol & amino acids

12. Coordinate Control of Cholesterol Uptake and Synthesis
Increased uptake of LDL-cholesterol results in:
inhibition of HMG-CoA reductase
reduced cholesterol synthesis
stimulation of acyl CoA:cholesterol acyl transferase (ACAT)
increased cholesterol storage
TG + C -> DG + CE
decreased synthesis of LDL-receptors
“down-regulation”
decreased LDL uptake

13. Heterogeneity of LDL-particles
Not all LDL-particles the same
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:
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)
Some drugs (niacin, fibrates) may be more effective at lowering small dense LDL.

14. LDL Peak Particle Diameter (nm)
LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study
6.2
(p<0.001)
Apo B
2.0
>120 mg/dl
LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study
In another analysis from the Quebec Cardiovascular Study, men were stratified by apo B level and LDL particle size. High apo B was associated with CHD, and the presence of both high apo B and small, dense LDL was associated with a marked increase in CHD risk. One interpretation of these findings is that concomitant interventions should be used both to lower apo B, such as with a statin, and to improve LDL particle size, such as with fibrates or high-dose statins. However, another interpretation is that if apo B is reduced to less than 120 mg/dL, LDL particle size no longer has an effect, perhaps because if there are few enough apo B-containing particles, it may not matter how atherogenic these particles are. This is a fairly controversial area, although a number of other epidemiological studies also suggest that this might be true. However, the effects of triglyceride level, for instance, which is strongly correlated to LDL particle size, appear to be considerably more important in people with high LDL/HDL ratio, apo B level, or total cholesterol level, as has been seen in the observational Paris Prospective Study and Prospective Cardiovascular Münster (PROCAM) Study and the interventional Helsinki Heart Study.
Reference:
Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation 1997;95:69-75.
1.0
1.0
<120 mg/dl
>25.64
<25.64
LDL Peak Particle Diameter (nm)
Lamarche B et al. Circulation 1997;95:69-75.

15. HDL Metabolism: Functions
Apoprotein exchange
provides apo C and apo E to/from VLDL and chylomicrons
Reverse cholesterol transport

16. Reverse cholesterol transport figure 19-6
Uptake of cholesterol from peripheral tissues (binding by apo-A-I)
Esterification of HDL-C by LCAT
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

17. Resolution of Clinical Case
Familial hypercholesterolemia (FH)
Family history
Early xanthomas and very high TC
Absence of LDL-receptors
Homozygous FH
Parent TC consistent with heterozygous 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
Combined liver/heart recommended because of advance CHD

19. Exam 2 Monday, July 18 Lipid Transport Cholesterol Metabolism Format
Chapter 19
MAAG chapter 54
Type 2 Diabetes and Insulin Resistance in Adipose
Effect on LPL causing hyperlipidemia
Signaling fault resulting in inappropriate lipolysis
Cholesterol Metabolism
Chapter 21
MAAG chapter 32
Format
Multiple choice questions
Short essay questions