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CETP as a Target in HDL-Raising Therapy: Lessons from APOE*3-Leiden.CETP Transgenic Mice
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CETP as a target in HDL-raising therapy
lessons from APOE*3-Leiden.CETP mice
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Outline of Presentation
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Outline of Presentation
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Lipoprotein metabolism
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Lipoprotein metabolism
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Role of CETP in lipoprotein metabolism
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Therapy of CVD-associated dyslipidemiamoney spent on drugs to treat dyslipidemia
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CVD-associated dyslipidemiamainly treated with statins
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Novel therapeutic strategiescurrently in development
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Outline of Presentation
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HDL-C is a strong inverse predictorof CHD risk at all levels of LDL-C
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Antiatherogenic properties of HDL
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First HDL-raising strategy: CETP inhibition
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CETP inhibitor: Torcetrapib
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Torcetrapib strongly increases HDL-C levelsPhase I studies in normolipidemic healthy volunteers
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Torcetrapib strongly increases HDL
but does not reduce atherosclerosis!
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Elucidation of (adverse) effects of torcetrapib in mice through translational research
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Wild-type mice:low (V)LDL and high HDL
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Mouse model for human-like
lipoprotein metabolism
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Structure apoE
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APOE*3-Leiden.CETP transgenic mice:human-like lipoprotein metabolism
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APOE*3-Leiden.CETP transgenic mice:
human-like lipoprotein metabolism
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APOE*3-Leiden.CETP mice:human-like lipoprotein metabolism
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Effect CETP expression on atherosclerosisstudy design
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CETP expression in APOE*3-Leiden mice aggravates diet-induced atherosclerosis
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Atherosclerosis development in E3L.CETP miceis not simply predicted from cholesterol exposure
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APOE*3-Leiden.CETP mouse:model for human-like lipoprotein metabolism
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Torcetrapib in E3L.CETP mice
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Torcetrapib decreases CETP activityOral gavage in solutol:ethanol:saline (10:10:80)
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Torcetrapib decreases CETP activityOral gavage in solutol:ethanol:saline (10:10:80) (10 mg/kg)
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Torcetrapib tends to decreases cholesterolDiet + 0.1% cholesterol + torcetrapib
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Torcetrapib increases HDL in E3L.CETP miceDiet + 0.1% cholesterol + 0.01% torcetrapib
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Effect of torcetrapib on atherosclerosis development in APOE*3-Leiden.CETP mice
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Torcetrapib reduces CETP activityand increases CETP mass
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Torcetrapib reduces CETP activity
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Torcetrapib reduces plasma total cholesteroland increases HDL-cholesterol
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Torcetrapib reduces atherosclerotic lesion area, but does not add to the effect of atorvastatin
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Torcetrapib reduces atherosclerotic plaque severity,but not beyond atorvastatin
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Torcetrapib increases MCP-1 content, monocyte adherence, and macrophage content of the plaque
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Torcetrapib decreases collagen content of the plaque, independent of smooth muscle cell content
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Torcetrapib induces an unstable lesion phenotype as compared to atorvastatin
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Torcetrapib tends to increasegeneral inflammatory status
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Torcetrapib increases generalinflammatory status and plasma aldosterone
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Torcetrapib increases plasma aldosterone viaclass-specific effect independent of CETP inhibition
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Outline of Presentation
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Current drugs that increase HDL-C levels
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Fenofibrate and atorvastatin
in E3L.CETP mice
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Fenofibrate
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Fenofibrate decreases TG in E3L.CETP miceDiet + 0.25% cholesterol + 0-0.04% fenofibrate (males)
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Fenofibrate increases HDL in E3L.CETP miceDiet + 0.25% cholesterol + fenofibrate (males)
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Fenofibrate increases HDL in E3L.CETP miceDiet + 0.25% cholesterol + 0.04% fenofibrate (males)
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Fenofibrate increases HDL in E3L.CETP miceDiet + 0.25% cholesterol + 0.04% fenofibrate (males)
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FF does not differentially affect HDL genesDiet + 0.25% cholesterol + 0.04% fenofibrate (males)
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Fenofibrate increases HDL in E3L.CETP miceDiet + 0.25% cholesterol + 0.04% fenofibrate (males)
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Atorvastatin in E3L.CETP mice
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Atorvastatin
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Atorvastatin decreases TC in E3L.CETP miceDiet + 0.1% cholesterol + atorvastatin (females)
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Atorvastatin increases HDL in E3L.CETP miceDiet + 0.25% cholesterol + 0.01% atorvastatin (males)
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Atorvastatin increases HDL in E3L.CETP miceDiet + 0.25% cholesterol + 0.01% atorvastatin (males)
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Atorva does not differentially affect HDL genesDiet + 0.25% cholesterol + 0.01% atorvastatin (males)
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Atorvastatin reduces CETP expressionDiet + 0.25% cholesterol + 0.01% atorvastatin (males)
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Atorvastatin reduces CETP mass and activityDiet + 0.25% cholesterol + atorvastatin (females)
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Mechanism underlying HDL-raising effectof statins and fibrates
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Niacin
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Niacin strongly reduces cardiac events
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Atheroprotective effect of niacin is accompanied by a large increase in HDL level
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Niacin potently increases plasma HDL levels
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Niacin does not affect HDL in E3L miceDiet + 0.1% cholesterol + 0.3% niacin (female mice)
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Niacin decreases TG and TC in E3L.CETPDiet + 0.1% cholesterol + niacin (female mice)
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Niacin decreases TG and TC in E3L.CETPDiet + 0.1% cholesterol + niacin (female mice)
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Niacin increases HDL in E3L.CETP miceDiet + 0.1% cholesterol + niacin (female mice)
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Niacin increases HDL in E3L.CETP miceDiet + 0.1% cholesterol + niacin (female mice)
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Niacin decreases clearance of 125I-apoAI-HDLDiet + 0.1% cholesterol + niacin (female mice)
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Niacin decreases liver lipidsDiet + 0.1% cholesterol + niacin (female mice)
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Niacin decreases plasma CETP activityDiet + 0.1% cholesterol + niacin (female mice)
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Niacin increases HDL particle sizeDiet + 0.1% cholesterol + niacin (female mice)
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Mechanism underlying HDL-raising effectof niacin
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Niacin causes regression of atherosclerosis
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Translational research: relation betweenliver lipid, CETP and HDL-C in humans
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Determination of liver TG byproton MR spectroscopy of the liver
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Pioglitazone and metforminequally reduce plasma apoB100 and TG
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Pioglitazone raises HDL-C,reduces CETP and reduces liver lipid
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Outline of Presentation
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Conclusions
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APOE*3-Leiden.CETP mouse
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APOE*3-Leiden.CETP mice
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Acknowledgments
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Thank you!
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The atherogenicity of CETP depends on TGProspective data from the Epic-Norfolk study
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CETP mutation Ile405Val increases HDL…
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… but increases CVD risk!
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Effect of CETP on VLDL levels seem to largely explain increased atherosclerosis
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Slide 94
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Effect of CETP expression on atherosclerosis in APOE*3-Leiden mice
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APOE*3-Leiden.CETP micealtered lipoprotein profile (female, chow diet)
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Effect CETP expression on atherosclerosisstudy design
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CETP expression increases plasma cholesterol and shifts cholesterol distribution
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Quantification of atherosclerosis development in heart valve area in aortic root
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CETP aggravates lesion severity in aortic rootWestern-type diet (19 weeks); HPS staining
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CETP increases atherosclerotic lesion areaWestern-type diet (19 weeks); HPS staining
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LXR agonist in E3L.CETP mice
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LXR agonist decreases HDL in E3L.CETPDiet + 0.25% cholesterol + 0.01% T0901317 (male mice)
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LXR agonist decreases HDL in E3L.CETPDiet + 0.25% cholesterol + 0.01% T0901317 (male mice)
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LXR agonist decreases HDL in E3L.CETPDiet + 0.25% cholesterol + 0.01% T0901317 (male mice)
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Torcetrapib
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Torcetrapib increases HDL in E3L.CETP miceOral gavage in solutol:ethanol:saline (10:10:80) (females)
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Torcetrapib tends to decreases cholesterolDiet + 0.1% cholesterol + torcetrapib (females)
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Torcetrapib increases HDL in E3L.CETP miceDiet + 0.1% cholesterol + 0.01% torcetrapib (females)
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CETP inhibitor Merck in CETP mice
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CETP-I increases HDL-C in CETP miceChow diet + 0.05% CETP inhibitor (~50 mg/kg)
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CETP-I increases HDL-C in CETP miceChow diet + 0.05% CETP inhibitor (male mice)
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CETP-I increases HDL-C in CETP miceDiet + 0….% cholesterol + …% CETP-I (male mice)
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Bile acids in E3L.CETP mice
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Bile acids decrease HDL-C in E3L.CETP miceChow diet + 0.5% TCA (male mice)
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Bile acids increase CETP in E3L.CETP miceChow diet + 0.5% TCA (male mice)
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Conclusions
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Human Lipoprotein Metabolism
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Lipoprotein metabolism – back to basics!
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Reduction of LDL cholesterol by statins (II)
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Lipoproteins - Composition
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Lipoproteins - Size
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Lipoproteins differ in size and density
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Lipoproteins differ in size and density
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Lipoprotein Metabolism
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Dyslipidemia
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Statins reduce LDL-cholesterol by inhibiting HMG-CoA reductase
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Factors known to reduce HDL-C levels (I)
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Factors known to reduce HDL-C levels (II)
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Anti-atherogenic activities of HDL particles (II)
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Anti-atherogenic activities of HDL particles (I)
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HDL is an anti-inflammatory agent
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Torcetrapib strongly increases HDL-C levelsPhase I studies in normolipidemic healthy volunteers (II)
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Torcetrapib: large phase III trial in patients
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Torcetrapib lacks anti-atherosclerotic efficacy!
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Potential explanations for failure of torcetrapib
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Lipoprotein Metabolism - mouse
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Lipoprotein Metabolism
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APOE*3-Leiden mouse
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Atherosclerosis development in APOE*3-Leiden mice depends on cholesterol exposure
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Rosuvastatin reduces plasma cholesterolin APOE*3-Leiden mice
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Rosuvastatin reduces atherosclerosis comparedto high and low cholesterol groups
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Rosuvastatin reduces expression ofmonocyte chemotactic protein-1 (MCP-1)
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Rosuvastatin reduces expression of MCP-1 compared to high and low cholesterol groups
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Rosuvastatin reduces serum amyloid A (SAA) compared to high and low cholesterol groups
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Regression of atherosclerosisin APOE*3-Leiden mice
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Introduction of CETP in APOE*3-Leiden mice
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Introduction of CETP in APOE*3-Leiden mice
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Overview of Presentation
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raising HDL: novel therapeutic targets
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raising HDL: novel therapeutic targets
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Experimental HDL-directed drugs
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ApoAIMilano (I)
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ApoAIMilano (II)
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D4F
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Niacin decreases plasma lipase activityDiet + 0.1% cholesterol + niacin (female mice)
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Therapy of CVD-associated dyslipidemiamarket for drugs to treat dyslipidemia
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Anti-atherogenic activities of HDL particles
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HDL plays role in reverse cholesterol transport
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Anti-atherogenic activities of HDL particles
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