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The role of the CETP protein in reverse
cholesterol transport and atherogenesis:
Is CETP good or bad?
Prof. Chris Packard
Western Infirmary
Glasgow, United Kingdom
CETP as a therapeutic target
Key considerations
•
•
•
•
Role of CETP in HDL and LDL physiology.
Natural CETP variation and CHD risk.
Epidemiology of CETP.
Pharmacodynamics of CETP regulation.
CETP in HDL physiology
Role in lipoprotein metabolism
CETP
CETP - a promiscuous plasma transfer
protein shuttling neutral lipid between
lipoproteins.
Macrophage
LCAT
LCAT
Nascent
HDL
ABCA1
After Brewer et al. Am J Cardiol 2003; 92:10K
CETP in HDL physiology
Role in reverse cholesterol transport
CE
CE
VLDLremnants/IDL/LDL
• CETP lacks intrinsic directionality.
• Metabolic gradients are maintained to promote net
transfer of CE from HDL to VLDL remnants and LDL.
CETP in HDL physiology
Lessons from nature
X
VLDLr/ IDL/
CETP deficiency in humans (prevalent in
Japanese) is often associated with very high
HDL chol and low LDL but link with CHD risk is
unclear (Barter et al ATVB (2003) 23:160-167)
Rodents have no CETP. HDL is
major cholesterol carrier. Natural
resistance to development of
atherosclerosis
HDL subfractions and reverse cholesterol
transport
2D analysis of plasma HDL
HDL2
HDL3
small, dense
HDL
pre
HDL
A1:phospholipid
CETP and the Atherogenic Lipoprotein Phenotype
ALP
type 2 diabetes, metabolic syndrome
•
•
•
•
Raised VLDL – hypercoagulability , raised PAI1.
Increased remnants – macrophage cholesterol deposition.
Small, dense LDL – retention in artery wall, readily oxidised.
Low HDL – impaired reverse cholesterol transport, reduced
antioxidant properties.
CETP central to development of ALP
Regulation of LDL metabolism by CETP
Packard et al. J Lipid Res 2000; 41:305-317
Sandhofer et al. Obesity 2006; 14:812-818
Origins of dyslipidemia in metabolic syndrome
FFA
Insulin
X
Moderate HTG
VLDL1
CE
TG
increased VLDL1
plasma TG>1.5
production
Remnants
CE
TG
LDL I/II
LDL I/II
CE
TG
CETP
TG
CE
HL (>15 U/l)
RT=5d
LDL III
CE
TG
Small, dense LDL
Packard and Shepherd (1997)
Regulation of HDL metabolism by CETP
Gut
Liver
Chylomicrons LpL
VLDL
TG
CE
HDL2
HDL2
CE
TG
TG
CE
CETP
LCAT
HL
PL, FA
PL,FC
CE
apoAI:PL
HDL3
pre B HDL
Regulation of HDL metabolism by lifestyle factors
Gut
Liver
Alcohol
Chylomicrons LpL
VLDL
Smoking
-
+
TG
CE
HDL2
HDL2
CETP
CE
TG
TG
+
LCAT
CE
Obesity
HL
PL, FA
PL,FC
HDL3
CE
apoAI:PL
pre B HDL
LDL and HDL size in inherited CETP deficiency
Lack of CETP leads to extreme changes in LDL and HDL structure
Bisgaier et al. J Lipid Res 1991; 32:21-33
CETP as a therapeutic target
Key considerations
•
•
•
•
Role of CETP in HDL and LDL physiology.
Natural CETP variation and CHD risk.
Epidemiology of CETP.
Pharmacodynamics of CETP regulation.
CETP as a major gene determining lipid levels
(Hepatic lipase)
Teslovich et al. Nature 2010; 466:707-713
CETP gene variation and HDL regulation
CETP variation in promoter region : C- common type; A - rare allele
CETP (mg/L)
CETP activity (nmol.L-1,s-1)
Whole group
(n=220)
CC
(n=51, 23.2%)
AC
(n=109, 49.5%)
AA
(n=60, 27.3%)
ANOVA
P value
2.39±0.81
2.96±0.96
2.26±0.67***
2.13±0.66***
<0.001
2.7 (1.9–3.9)
3.4 (2.4–4.8)
2.7 (1.8–3.8)***
2.6 (1.7–3.5)***
0.007
High-density lipoprotein subfractions in the population and CETP genotype groups
Genotype
CC
AC
AA
Total
HDL-TG, mmol/L (n=115)
0.21±0.07
0.20±0.06
0.23±0.07
0.21±0.06
HDL-C, mmol/L (n=219)*
1.36±0.31
1.42±0.30
1.60±0.43‡
1.44±0.34
HDL2 mass, mg/100 mL (n=215)*
77±39
87±48
112±59
89±50
HDL3 mass, mg/100 mL (n=215)
266±63
263±54
272±65
266±59
Freeman et al. (1994) ATVB 14;336-344; Dullaart et al (2008) Scan J Clin Lab Invest 68;99-105
CETP Genetics and CHD risk
Meta-analysis of 92 studies of CETP genotype, lipid levels and
CHD risk in general population.
Inheritance of one ‘A’ allele in
CETP gene associated with:• 9.7% lower CETP mass
• 8.6% lower CETP activity
• 4.5% higher HDLchol
• 2.4% higher apoA1
• Odds ratio for CHD per A
allele of 0.95 (0.92-0.99)
Thompson et al. JAMA 2008; 299:2777-2788
CETP genetics and CHD risk
Influence of background statin therapy
Regieli et al. Eu Heart J 2008; 29:2792-2799
CETP as a therapeutic target
Key considerations
•
•
•
•
Role of CETP in HDL and LDL physiology.
Natural CETP variation and CHD risk.
Epidemiology of CETP.
Pharmacodynamics of CETP regulation.
Epidemiology of CETP
Framingham study
Higher CETP activity
Lower risk
Vasan et al. Circulation 2009; 120:2414-2420
CETP mass and CHD incidence in
PROVE-IT
Subjects on 40 md pravastatin / 80mg atorvastatin :
Hazard ratio per SD increase in CETP mass = 0.77 (P=0.005)
Interaction between CETP mass and LDL chol (P=0.007)
Khera et al. Am J Cardiol 2010; 106:451-456
CETP: Friend or Foe ?
?
?
• Which pathway is quantitatively more important in reverse
cholesterol transport in man, particularly in statin treated subjects ?
• Is CETP required to be active when LDL is low ?
CETP as a therapeutic target
Key considerations
•
•
•
•
Role of CETP in HDL and LDL physiology.
Natural CETP variation and CHD risk.
Epidemiology of CETP.
Pharmacodynamics of CETP regulation.
Pharmacodynamics of CETP regulation
Cys 13 – dalcetrapib binding site
Lipid tunnel
Anacetrapib (MSD)
CETP crystal structure
Dalcetrapib (Roche)
Dalcetrapib
Torcetrapib
Anacetrapib
9000 nmo/l
50 nmol/l
57 nmol/l
CETP inhibition
37.2%
≥80%
90%
HDL-C increase
33.9%
91%
129%
Blood pressure increase
No
Yes
No
Increases aldosterone
production (in vitro)
No
Yes
No
IC50
Qui et al (2007) Nat Struct Mol Biol 14;106-112, Ranaletta et al (2010) J Lipid Res on line, Okamoto et al. Nature. 2000;406:203–207, Clark et al. J Lipid Res. 2006;47:537–552,
Masson D. Curr Opin Invest Drugs. 2009;10:980-987, Grooth et al. Circulation. 2002;105:2159–2165, Clark et al. Arterioscler Thromb Vasc Biol. 2004;24:490–497; Krishna et al.
Lancet. 2007;370:1907-1914, Stein et al. Am J Cardiol. 2009;104:82–91, Barter et al. N Engl J Med. 2007;357:2109–2122, Forrest et al. Br J Pharmacol 2008;154:1465–1473
Effects of CETP regulation on
plasma lipids
Dalcetrapib
Anacetrapib
HDL chol
+27%
+138%
LDL chol
-5%
-40%
ApoA1
+13%
+45%
Triglyceride
+1%
-7%
0
-39%
Lp(a)
Robinson. Exp Opin Invest Drug 2010; 19:795-805
Cannon et al. NEJM 2010; 363:2406-2415
CETP deficiency and apoB metabolism
Lipoprotein kinetic studies in CETP deficient homozygotes
FCR LDL from CETP(-) = 0.41 pools/d
FCR LDL from normal = 0.60 pools/d
LDL from CETP(-) has reduced clearance rate, reduced IDL synthesis,
increased removal rate for LDL in CETP (-) despite LDL abnormality
Ikewaki et al. J Clin Invest 1995; 96:1573-1581
Differential regulation of CETP
HDL3 – HDL2 transfer
Impact on pre-HDL
Niesor et al. J Lipid Res 2010; 51:3443-3454
CETP, HDL substructure and
atheroprotection
CETP, Hepatic lipase
A1:phospholipid
pre HDL
LCAT, ABCA1, LpL
HDL3
small,dense HDL
HDL2
HDL INHIBIT ADHESION MOLECULE EXPRESSION
Monocyte
LDL
Adhesion
Molecule
Endothelium
MCP-1
Cytokines
Vessel lumen
LDL
HDL INHIBIT
OXIDATION OF LDL
MODIFIED LDL
Intim
a
Macrophage
Foam Cell
HDL PROMOTE CHOLESTEROL EFFLUX
(after Barter et al)
Testing the HDL paradigm
Outcome scenarios
60
• Scenario 1 – Treatment effect independent
of baseline HDL. Rx given to all at a single
dose.
50
Males
40
30
20
10
0
30
45
60
75
90
• Scenario 2 – Risk reduction dependent on
baseline HDL; no benefit at HDLc > 50
mg/dl. Need to measure HDL accurately.
• Scenario 3 – Risk reduction dependent on
baseline CRP; no benefit if CRP > 3 mg/dl
(low HDL linked to inflammation not
reduced reverse cholesterol transport).
Danesh et al (2009) JAMA 302:1993-2000
Summary -1
Metabolic impact of CETP variation
• CETP is a major regulator of lipoprotein structure and
composition.
• Lower CETP activity is associated with larger LDL and HDL
species.
• Inherited deficiency of CETP in the homozygous form is linked
to the appearance of very small LDL and very large HDL
subfractions.
• Higher CETP activity may play a role in generating the
dyslipidemia of metabolic syndrome.
Summary - 2
CETP as a target to reduce atherosclerosis
• Studies in general population indicate that CETP gene
variants linked to lower activity are associated with reduced
risk. This may not be the case in statin treated patients.
• Epidemiological studies demonstrate a variable association
between CETP activity / mass and CHD risk.
• The impact of CETP modulation on atherosclerosis may
depend on the metabolic context.
• Outcome studies are required to demonstrate clinical benefit
of drugs that modify CETP activity.