Manfredi Rizzo, MD, PhDAssociate Professor of Internal Medicine
Faculty of Medicine, University of Palermo, Italy&
Affiliate Associate Professor of Internal Medicine School of Medicine, University of South Carolina, USA
MetabolismandAtherogenicPropertiesofLDL
DISCLOSURE
I have given talks, attended conferences and participated in advisory boards and trials sponsored by - Amgen- Astra Zeneca- Boehringer-Ingelheim- Lilly - Meda Pharma- Merck - Novo Nordisk- Roche - Servier
EPIDEMIOLOGY
courtesy of Prof. R. Santos
METABOLISM
Lipoprotein Subclasses
courtesy of Prof. R. Santos
courtesy of Prof. R. Santos
Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Lipoprotein Metabolism
- TGs - TGs
More Triglyceride Less Triglyceride
Lower Cholesterol Concentration
Higher Cholesterol Concentration
- Apolipoproteins
LPL HL
LDL Phenotype
• 7 distinct LDL subclasses
• Two primary LDL phenotypes (pattern A & pattern B)
• Pattern A is predominantly larger, more buoyant LDL
• Pattern B is primarily smaller, more dense LDL
Larger & More Buoyant
Smaller & More DenseEur Heart J 1998;19(Suppl A):A24-A30. Circulation
1996;94:2351-4.
Distribution of LDL particles according to size and density
B.A. Griffin
27.5 27.0 25.5 24.2 21.8
LDL-I II III IV
LDL Particle Size (Diameter nm)
1.065
1.025 1.034 1.044 1.060
Density (g/ml)
Healthy femaleMaleCAD patient
Rizzo M et al. Eur J Clin Invest 2003;33:126-33
LDL size and HDL-c
230
240
250
260
270
280
290
300LD
L Si
ze (Å
)
20 30 40 50 60 70 80 90
r= +.319; p< 0.0001
230
240
250
260
270
280
290
300
0 50 100 150 200 250 300 350 400
r= -.459; p< 0.0001
LDL size and TG
LDL
Size
(Å)
Rizzo M, Berneis K. Low-density-lipoproteins size and cardiovascular risk assessment QJM 2006; 99: 1-14.
Gradient Gel Electrophoresis (GGE)
Prof. Rizzo Lab
LDL-C Doubly Underestimates CV Risk in case of Small, Dense LDL
Large LDL Small, Dense LDL
Apo BLDL-C
130 mg/dL
Fewer Particles &Less Risk/Particle
More Particles &More Risk/Particle
CholesterolEster
More Apo B
Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.
Lipid profile:TC 198 mg/dLLDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dL
Lipid profile:TC 210 mg/dLLDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dL
Low-Density Lipoprotein (LDL) Consists of Multiple Distinct Subclasses Differing in Size and Lipid Content*
Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Association with Cardiovascular Disease Risk
Large
Small
Less Atherogenic
* Distribution of subclasses isindependent of LDL-C.
More Atherogenic
12
3
4
l ↓ clearance by LDL-Rl ↑ arterial entry l ↑ arterial retentionl ↑ oxidation
Increased small, dense, LDL particles associated with reduced IHD survival
St-Pierre AC et al. Arterioscler Thromb Vasc Biol. 2005;25:553-9.
N = 2072 men without IHD at baseline;13-year follow-up
1.00
0.90
0.80
Survivalprobabilities
Follow-up (years)0 2 4 6 8 10 12
P < 0.0001
Levels of smal dense LDL low normal high
IHD = ischemic heart disease
courtesy of Prof. R. Santos
BLOOD CHOLESTEROL HOMEOSTASIS
LDL
Brown MS, et al. Proc Natl Acad Sci 1979;76:3330-3337. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547
Hepatic LDLRs Play a Central Role in Cholesterol Homeostasis
LDL particles consist mostly of cholesteryl esters packaged with a protein moiety called apolipoprotein B (apoB), with 1 apoB molecule in each LDL particle.
LDL particles are the primary carriers of plasma cholesterol in humans, and high LDL levels have a strong and direct relationship with the development of atherosclerosis.
The liver is responsible for the clearance and catabolism of plasma LDL, and hepatocyte expression of LDL receptors (LDLRs) are central to this process by binding and removing LDL from the plasma.
LDL/LDLR complex is internalized into the hepatocyte via clathrin-coated vesicles, thereby removing LDL from the blood. The affinity of the hepatic LDL receptor for apoB on LDL enables LDLRs to clear plasma LDL effectively.
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
Clathrin-coated vesicles containing internalized LDL/LDLR complexes fuse with endosomes, resulting in dissociation of the LDLs from LDLRs due to the acidic environment.
The free LDLRs then recycle back to the surface of the hepatocyte to bind and clear additional LDL from the blood.
Free LDL particles in the endosomes are transported to the lysosomes and degraded into lipids and amino acids.
The ability of hepatic LDLRs to be recycled is a key determinant of hepatic efficacy in lowering plasma LDL.
Brown MS, et al. Proc Natl Acad Sci 1979;76:3330-3337. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
Brown MS, et al. Proc Natl Acad Sci 1979;76:3330-3337. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547
PCSK9 is a proprotein that is produced in hepatocytes, and secreted into the plasma as functional PCSK9.
Extracellular PCSK9 binds to the LDLR on the surface of the hepatocyte and is internalized within the endosome.
LDLR/PCSK9 complex is routed to lysosome for degradation, preventing recycling of LDLR back to hepatocyte surface.
By preventing LDLRs from recycling back to the surface, PCSK9 reduces the concentration of LDLRs on the surface of hepatocytes, resulting in a lower LDL clearance rate and elevated levels of plasma LDL.
EPIDEMIOLOGY
Nature Reviews Cardiology 11, 130–132 (2014)
CONCLUSIONS
• Causal Risk factor for CVD
• Heterogeneous group of particles
• Levels regulated by complex mechanisms
• Pro-atherogenic properties-Endothelial dysfunction-Pro-inflammatory-Pro-thrombotic
(• LDL-C reduction is anti-atherogenic)