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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.