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Focus on high density lipoproteins
- 1. Focus on High Density LipoproteinsFocus on High Density Lipoproteins Dr. Sachin Verma MD, FICM, FCCS, ICFC Fellowship in Intensive Care Medicine Infection Control Fellows Course Consultant Internal Medicine and Critical Care Ivy Hospital Sector 71 Mohali Web:- http://www.medicinedoctorinchandigarh.com Mob:- +91-7508677495
- 2. Lipoprotein Classes and AtherosclerosisLipoprotein Classes and Atherosclerosis Chylomicrons,Chylomicrons, VLDL, and theirVLDL, and their catabolic remnantscatabolic remnants LDLLDL HDLHDL Pro-atherogenicPro-atherogenic Anti-atherogenicAnti-atherogenic
- 3. IntroductionIntroduction High-density lipoprotein (HDL) is one of the five major groups of lipoproteins that enables lipids like cholesterol and triglycerides to be transported within the water based blood stream. HDL can remove cholesterol from atheroma within arteries and transport it back to the liver for excretion or re- utilization. Therefore HDL is also called as good cholesterol.
- 4. Structure of HDLStructure of HDL HDL is the smallest of theHDL is the smallest of the lipoprotein particles.lipoprotein particles. HDL particles have a size of 6-HDL particles have a size of 6- 12.5 nanometers12.5 nanometers They have high density ~1.12They have high density ~1.12 mainly because of highmainly because of high proportion of proteinsproportion of proteins
- 5. HDL StructureHDL Structure HDL contains approximatelyHDL contains approximately 55% protein55% protein 3-15% triglycerides3-15% triglycerides 26-46% phospholipids26-46% phospholipids 15-30% cholesteryl esters15-30% cholesteryl esters 2-10% cholesterol.2-10% cholesterol.
- 6. HDL StructureHDL Structure HDL contains several types ofHDL contains several types of apolipoproteins including:apolipoproteins including: apo-AIapo-AI Apo-AIIApo-AII apo-CIapo-CI apo-CIIapo-CII apo-Dapo-D apo-E.apo-E. Their most abundant apolipoproteins areTheir most abundant apolipoproteins are apo A-I and apo A-II.apo A-I and apo A-II.
- 7. HDL StructureHDL Structure Cholesterol acceptor Cholesterylester donor Reverse Cholesterol Transport (RCT) Anti-thrombotic HDL-C Protection against oxidation Modulation of endothelial function Protection of the vessel wall Endothelial repair Anti-inflammatory
- 10. Alpha HDL BuoyancyAlpha HDL Buoyancy
- 11. HDL SynthesisHDL Synthesis Synthesis of new high-densitySynthesis of new high-density lipoprotein (HDL) particles beginslipoprotein (HDL) particles begins with the secretion ofwith the secretion of apolipoprotein A-I (apo A-I) fromapolipoprotein A-I (apo A-I) from the liver.the liver. The resulting HDL2 (larger, lessThe resulting HDL2 (larger, less dense particles) and HDL3dense particles) and HDL3 (smaller, more dense particles) can(smaller, more dense particles) can serve as acceptors for ABCG1-serve as acceptors for ABCG1- mediated cholesterol efflux26.mediated cholesterol efflux26.
- 12. Reverse Cholesterol Transport: Cellular levelReverse Cholesterol Transport: Cellular level
- 13. Role of HDL in lipid redistribuionRole of HDL in lipid redistribuion Role of high-density lipoprotein (HDL) in the redistribution of lipids from cells with excess cholesterol to cells requiring cholesterol or to the liver for excretion. The reverse cholesterol transport pathway is indicated by arrows (net transfer of cholesterol from cells HDL LDL liver).➙ ➙ ➙
- 14. Reverse Cholesterol Transport: Cellular levelReverse Cholesterol Transport: Cellular level Several steps in the metabolism of HDL can contribute to the transport of cholesterol from lipid laden macrophages of atherosclerotic arteries, termed foam cells to the liver for secretion into the bile. This pathway has been termed reverse cholesterol transport and is considered as the classical protective function of HDL towards atherosclerosis.
- 15. Reverse Cholesterol Transport: Cellular levelReverse Cholesterol Transport: Cellular level High-density lipoprotein (HDL) cholesterol promotes and facilitates the process of reverse cholesterol transport (RCT), whereby excess macrophage cholesterol is effluxed to HDL and ultimately returned to the liver for excretion. Efflux to nascent and mature HDL occurs via the transporters ABCA1 and ABCG1, respectively. The HDL cholesterol is returned to the liver via the hepatic receptor SR-BI or by transfer to apolipoprotein (apo) B–containing lipoproteins by the action of cholesteryl ester transfer protein (2).
- 16. HDL metabolism and reverse cholesterolHDL metabolism and reverse cholesterol transporttransport
- 17. Role of Hepatic Lipase and Lipoprotein LipaseRole of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolismin HDL Metabolism CM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein; HL = hepatic lipase; IDL = intermediate-density lipoprotein; LPL = lipoprotein lipase; PL = phospholipase; TG = triglyceride B Kidney Endothelium B TG CMR/IDL C-II CM/VLDL HL LPL A-I CE TG HDL2 PL A-I CE HDL3 PL Phospholipids and apolipoproteins
- 18. HDL Metabolism in CETP DeficiencyHDL Metabolism in CETP Deficiency A-I CE FCFC LCAT A-I Macrophage B Delayed catabolism CETP ABC1 HDL VLDL/LDL Nascent HDL CE
- 19. Targeting HDL MetabolismTargeting HDL Metabolism Improve HDL function - apoAI Milano - apoAI mimetic peptides Increase HDL synth. or infuse rHDL - apoM? ETC216 - LPL LUV’s - apoAI Delipidated HDL Extend/reduce circulation Time Block clearance - trimeric apoAI - SR-BI Modulate PL - phosphatidyl inositol - sPLA2 Improve lipidation maturation - ABCA1 - ABCG1 - LCAT HDL remodeling - HL, EL, PLTP? - apoCI? - CETP PL,FC,CE,apo’s PL,FC,CE,apo’s Renal clearance
- 20. CETP Inhibition and Lipoprotein MetabolismCETP Inhibition and Lipoprotein Metabolism
- 21. Cholesterol efflux and reverse cholesterolCholesterol efflux and reverse cholesterol transport is modulated by two receptorstransport is modulated by two receptors
- 22. HDL-C Protection Against AtherosclerosisHDL-C Protection Against Atherosclerosis Acts by inhibitingActs by inhibiting OxidationOxidation InflammationInflammation Activation of endotheliumActivation of endothelium CoagulationCoagulation Platelet aggregationPlatelet aggregation
- 23. Inhibitory properties of HDLInhibitory properties of HDL
- 24. HDL-C: Anti-atherogenic effectsHDL-C: Anti-atherogenic effects HDL inhibits expression of adhesion molecules HDL inhibits oxidation of LDL HDL promotes cholesterol efflux HDL activates eNOS LDL LDL Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines Intima Foam Cell NO NO NO NO RCT
- 25. HDL metabolism: 5 key genesHDL metabolism: 5 key genes
- 26. HDL: Apo AI-rich particlesHDL: Apo AI-rich particles
- 27. Anti-inflammatory effects of HDLAnti-inflammatory effects of HDL
- 28. Antioxidant Action of HDL cholesterolAntioxidant Action of HDL cholesterol
- 29. Antioxidant Action of HDL cholesterolAntioxidant Action of HDL cholesterol
- 30. LDL LDL Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. Endothelium Vessel LumenMonocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines HDL Prevents Formation of Foam CellsHDL Prevents Formation of Foam Cells IntimaHDL Promote Cholesterol Efflux Foam Cell
- 31. LDL LDL Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines Inhibition of Adhesion MoleculesInhibition of Adhesion Molecules Intima HDL Inhibit Oxidation of LDL HDL Inhibit Adhesion Molecule Expression Foam Cell HDL Promote Cholesterol Efflux
- 32. LDL LDL Endothelium Vessel LumenMonocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines HDL Inhibits the Oxidative Modification of LDLHDL Inhibits the Oxidative Modification of LDL Foam Cell HDL Promote Cholesterol Efflux Intima HDL Inhibit Oxidation of LDL
- 33. Additional Anti-inflammatory Properties of HDLAdditional Anti-inflammatory Properties of HDL HDL bind and neutralizesHDL bind and neutralizes proinflammatoryproinflammatory lipopolysaccharideslipopolysaccharides The acute phase reactantThe acute phase reactant SAA binds to plasmaSAA binds to plasma HDL, which possiblyHDL, which possibly neutralizes the effects ofneutralizes the effects of SAASAA 1. Baumberger C et al. Pathobiology 1991;59:378-383. 2. Benditt EP et al. Proc Natl Acad Sci U S A 1977;74:4025-4028
- 34. Apo A-I protects against atherosclerosisApo A-I protects against atherosclerosis
- 35. Recommended range of HDLRecommended range of HDL The American Heart Association, NIH and NCEP provides a set ofThe American Heart Association, NIH and NCEP provides a set of guidelines for fasting HDL levelsguidelines for fasting HDL levels Level mg/dLLevel mg/dL Level mmol/LLevel mmol/L InterpretationInterpretation <40 for men, <50 for<40 for men, <50 for womenwomen <1.03<1.03 Low HDL cholesterol,Low HDL cholesterol, heightened risk for heart diseaseheightened risk for heart disease 40–5940–59 1.03–1.551.03–1.55 Medium HDL levelMedium HDL level >60>60 >1.55>1.55 High HDL level, optimalHigh HDL level, optimal condition considered protectivecondition considered protective against heart diseaseagainst heart disease
- 36. Relationship between HDL cholesterol and CHD events.Relationship between HDL cholesterol and CHD events. Data from the Framingham StudyData from the Framingham Study RiskofCHD Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. 3 2 1 4 Equivalent Risk
- 37. Major cardiovascular event frequency byMajor cardiovascular event frequency by LDL-C and HDL-C levels in TNT studyLDL-C and HDL-C levels in TNT study
- 38. Causes of Low HDLCauses of Low HDL
- 39. Steps to Improve HDL LevelSteps to Improve HDL Level Life style modificationsLife style modifications – ExerciseExercise – AlcoholAlcohol – Smoking cessationSmoking cessation DrugsDrugs – NiacinNiacin – FibratesFibrates – StatinsStatins – CETP inhibitorsCETP inhibitors – ApoA-1 Milano/ApoA-1mimeticApoA-1 Milano/ApoA-1mimetic
- 40. HDL-C levels are modifiable by the quantity andHDL-C levels are modifiable by the quantity and quality of exercisequality of exercise
- 41. HERITAGE STUDY: Effects of 20 wks of endurance exercise trainingHERITAGE STUDY: Effects of 20 wks of endurance exercise training on lipid profileon lipid profile
- 42. Smoking cessation increases only HDL-C, but not TC,LDL-C or TGSmoking cessation increases only HDL-C, but not TC,LDL-C or TG
- 43. Mechanism of action of nicotinic acidMechanism of action of nicotinic acid
- 44. Fenofibrate & gemfibrozil are derivatives of fibric acid that lower TGs and increase HDL levels. Fenofibrate is more effective at lowering LDL & TGs. FibratesFibrates
- 45. Mechanism of Action of FenofibrateMechanism of Action of Fenofibrate
- 46. Statin drugs are structural analogs of HMG-CoAStatin drugs are structural analogs of HMG-CoA
- 47. Statin Evidence: Landmark Statin TrialsStatin Evidence: Landmark Statin Trials
- 48. Statin Evidence: Expanding BenefitsStatin Evidence: Expanding Benefits
- 49. Statin Evidence: BenefitsStatin Evidence: Benefits • The statin trials have demonstrated significant decreases in CVDThe statin trials have demonstrated significant decreases in CVD morbidity and mortality.morbidity and mortality. • Reduction in CVD events has been demonstrated in patientsReduction in CVD events has been demonstrated in patients with stable CHD as well as acute coronary syndrome patients.with stable CHD as well as acute coronary syndrome patients. • Additionally, lowering LDL-C to target levels has beneficialAdditionally, lowering LDL-C to target levels has beneficial effects in patients with normal or moderately elevated LDL-C.effects in patients with normal or moderately elevated LDL-C.
- 50. Drug ClassDrug Class LDL-CLDL-C HDL-CHDL-C TriglyceridesTriglycerides Statins*Statins* 18% to 60%18% to 60% 5% to 15%5% to 15% 7% to 37%7% to 37% Bile AcidBile Acid 15% to 30%15% to 30% 3% to 5%3% to 5% No change orNo change or SequestrantsSequestrants increaseincrease Nicotinic AcidNicotinic Acid 5% to 25%5% to 25% 15% to 35%15% to 35% 20% to 50%20% to 50% Fibric AcidsFibric Acids 5% to 20%5% to 20% 10% to 20%10% to 20% 20% to 50%20% to 50% Statin Efficacy: Lipid LoweringStatin Efficacy: Lipid Lowering Adapted from NCEP Expert Panel. JAMA. 2001;285:2486-2497. v v v v v v v v v v v
- 51. Statin Efficacy: ACCESSStatin Efficacy: ACCESS
- 52. DisclaimerDisclaimer The data, images, graphs and tables provided in this presentation has been developed by clinicians andThe data, images, graphs and tables provided in this presentation has been developed by clinicians and medical writers. It has also been validated by experts. Although great care has been taken in compilingmedical writers. It has also been validated by experts. Although great care has been taken in compiling checking the information, the authors, BioQuest and its servants or agents, and sponsors shall not bechecking the information, the authors, BioQuest and its servants or agents, and sponsors shall not be responsible or in anyway, liable for any errors, omissions on inaccuracies in the publication whether arisingresponsible or in anyway, liable for any errors, omissions on inaccuracies in the publication whether arising from negligence or otherwise however, or for any consequences arising there from. The inclusion or exclusionfrom negligence or otherwise however, or for any consequences arising there from. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in anyof any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields.particular field or fields. The data, images and illustrations are provided in their original form. Wherever applicable, the relevantThe data, images and illustrations are provided in their original form. Wherever applicable, the relevant sources and the details of the original copyright owners are provided for the reference of the readers. Shouldsources and the details of the original copyright owners are provided for the reference of the readers. Should you wish to recreate the data, images, graphs and tables, you are advised to contact the respective authors oryou wish to recreate the data, images, graphs and tables, you are advised to contact the respective authors or service providers wherever necessary. USV or BioQuest will not be liable for any consequences arising fromservice providers wherever necessary. USV or BioQuest will not be liable for any consequences arising from the unauthorized usage of this data.the unauthorized usage of this data.
Hinweis der Redaktion
- HDL is a class of heterogeneous lipoprotein s containing approximately equal amounts of lipid and protein.1 HDL particles are characterized by high density (>1.063 g/mL) and small size (Stoke’s diameter =5 to 17 nm). The various HDL subclasses vary in quantitative and qualitative content of lipids, apo lipoprotein s, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge, and antigenicity. Most of apo lipoprotein A-I (apo A-I), the predominant HDL protein, migrates in agarose gels with -electrophoretic mobility and is designated –LpA-I. This fraction accounts for almost all of the cholesterol quantified in the clinical laboratory as HDL-C. -HDL can be further fractionated by density into HDL2 and HDL3, by size, or by apo lipoprotein composition. Approximately 5% to 15% of apo A-I in human plasma is associated with particles with pre–ß-electrophoretic mobility. These can be further differentiated into pre–ß1-LpA-I, pre–ß2-LpA-I, and pre–ß3-LpA-I particles. These lipid-poor particles are increased in extravascular compartments where reverse cholesterol transport takes place Source: Baylor College of Medicine, Lipids Online (January 29, 2001). "Heterogeneity of HDL". http://www.lipidsonline.org/slides/slide01.cfm?q=apolipoprotein&dpg=59. Retrieved February 20 2006.
- HDL is a class of heterogeneous lipoprotein s containing approximately equal amounts of lipid and protein.1 HDL particles are characterized by high density (>1.063 g/mL) and small size (Stoke’s diameter =5 to 17 nm). The various HDL subclasses vary in quantitative and qualitative content of lipids, apo lipoprotein s, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge, and antigenicity. Most of apo lipoprotein A-I (apo A-I), the predominant HDL protein, migrates in agarose gels with -electrophoretic mobility and is designated –LpA-I. This fraction accounts for almost all of the cholesterol quantified in the clinical laboratory as HDL-C. -HDL can be further fractionated by density into HDL2 and HDL3, by size, or by apo lipoprotein composition. Approximately 5% to 15% of apo A-I in human plasma is associated with particles with pre–ß-electrophoretic mobility. These can be further differentiated into pre–ß1-LpA-I, pre–ß2-LpA-I, and pre–ß3-LpA-I particles. These lipid-poor particles are increased in extravascular compartments where reverse cholesterol transport takes place Source: Baylor College of Medicine, Lipids Online (January 29, 2001). "Heterogeneity of HDL". http://www.lipidsonline.org/slides/slide01.cfm?q=apolipoprotein&dpg=59. Retrieved February 20 2006.
- HDL is a class of heterogeneous lipoprotein s containing approximately equal amounts of lipid and protein.1 HDL particles are characterized by high density (>1.063 g/mL) and small size (Stoke’s diameter =5 to 17 nm). The various HDL subclasses vary in quantitative and qualitative content of lipids, apo lipoprotein s, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge, and antigenicity. Most of apo lipoprotein A-I (apo A-I), the predominant HDL protein, migrates in agarose gels with -electrophoretic mobility and is designated –LpA-I. This fraction accounts for almost all of the cholesterol quantified in the clinical laboratory as HDL-C. -HDL can be further fractionated by density into HDL2 and HDL3, by size, or by apo lipoprotein composition. Approximately 5% to 15% of apo A-I in human plasma is associated with particles with pre–ß-electrophoretic mobility. These can be further differentiated into pre–ß1-LpA-I, pre–ß2-LpA-I, and pre–ß3-LpA-I particles. These lipid-poor particles are increased in extravascular compartments where reverse cholesterol transport takes place Source: Baylor College of Medicine, Lipids Online (January 29, 2001). "Heterogeneity of HDL". http://www.lipidsonline.org/slides/slide01.cfm?q=apolipoprotein&dpg=59. Retrieved February 20 2006.
- HDL is a class of heterogeneous lipoprotein s containing approximately equal amounts of lipid and protein.1 HDL particles are characterized by high density (>1.063 g/mL) and small size (Stoke’s diameter =5 to 17 nm). The various HDL subclasses vary in quantitative and qualitative content of lipids, apo lipoprotein s, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge, and antigenicity. Most of apo lipoprotein A-I (apo A-I), the predominant HDL protein, migrates in agarose gels with -electrophoretic mobility and is designated –LpA-I. This fraction accounts for almost all of the cholesterol quantified in the clinical laboratory as HDL-C. -HDL can be further fractionated by density into HDL2 and HDL3, by size, or by apo lipoprotein composition. Approximately 5% to 15% of apo A-I in human plasma is associated with particles with pre–ß-electrophoretic mobility. These can be further differentiated into pre–ß1-LpA-I, pre–ß2-LpA-I, and pre–ß3-LpA-I particles. These lipid-poor particles are increased in extravascular compartments where reverse cholesterol transport takes place Source: Baylor College of Medicine, Lipids Online (January 29, 2001). "Heterogeneity of HDL". http://www.lipidsonline.org/slides/slide01.cfm?q=apolipoprotein&dpg=59. Retrieved February 20 2006.
- HDL is a class of heterogeneous lipoprotein s containing approximately equal amounts of lipid and protein.1 HDL particles are characterized by high density (>1.063 g/mL) and small size (Stoke’s diameter =5 to 17 nm). The various HDL subclasses vary in quantitative and qualitative content of lipids, apo lipoprotein s, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge, and antigenicity. Most of apo lipoprotein A-I (apo A-I), the predominant HDL protein, migrates in agarose gels with -electrophoretic mobility and is designated –LpA-I. This fraction accounts for almost all of the cholesterol quantified in the clinical laboratory as HDL-C. -HDL can be further fractionated by density into HDL2 and HDL3, by size, or by apo lipoprotein composition. Approximately 5% to 15% of apo A-I in human plasma is associated with particles with pre–ß-electrophoretic mobility. These can be further differentiated into pre–ß1-LpA-I, pre–ß2-LpA-I, and pre–ß3-LpA-I particles. These lipid-poor particles are increased in extravascular compartments where reverse cholesterol transport takes place Source: Baylor College of Medicine, Lipids Online (January 29, 2001). "Heterogeneity of HDL". http://www.lipidsonline.org/slides/slide01.cfm?q=apolipoprotein&dpg=59. Retrieved February 20 2006.
- Synthesis of new high-density lipoprotein (HDL) particles begins with the secretion of apolipoprotein A-I (apoA-I) from the liver. Fibrates have been shown to increase the expression of apoA-I in human hepatocytes150, 151. Lipid-free or lipid-poor apoA-I can subsequently serve as an acceptor for ABC transporter A1 (ABCA1)-mediated lipid efflux from hepatocytes or macrophages. Infusion of apoA-I has been shown to attenuate atherosclerosis in animals101 and possibly in humans31. ABCA1-mediated lipid efflux from macrophages can also be enhanced by transcriptional upregulation of this lipid transporter through the nuclear receptors liver X receptor (LXR)/retinoid X receptor (RXR)18 or retinoic acid receptor- (RAR)128. ABCA1-mediated efflux of cholesterol and phospholipids results in the formation of pre- or nascent HDL particles that are further modified by lecithin-cholesterol acyltransferase (LCAT). The resulting HDL2 (larger, less dense particles) and HDL3 (smaller, more dense particles) can serve as acceptors for ABCG1-mediated cholesterol efflux26. Expression of this transporter can also be stimulated by LXR activation152. Infusion of recombinant phospholipid–apoA-I complexes31 and large unilamellar phospholipid vesicles (LUVs)153 have been shown to increase HDL levels, presumably by acting as acceptors for ABCG1-mediated cholesterol efflux. Cholesterol esters from HDL can be transferred to apoB-containing lipoproteins by the action of cholesteryl ester transfer protein (CETP). Inhibition of CETP in humans has recently been shown to increase HDL and lower low-density lipoprotein (LDL) cholesterol84. The catabolism of HDL can also be inhibited by nicotinic acid through a mechanism that is largely unknown. Finally, HDL cholesterol can be taken up by the liver and subsequently secreted into the bile in a process that is mediated by scavenger receptor BI (SR-BI).
- Several steps in the metabolism of HDL can contribute to the transport of cholesterol from lipid laden macrophages of atherosclerotic arteries, termed foam cells to the liver for secretion into the bile. This pathway has been termed reverse cholesterol transport and is considered as the classical protective function of HDL towards atherosclerosis.
- Role of high-density lipoprotein (HDL) in the redistribution of lipids from cells with excess cholesterol to cells requiring cholesterol or to the liver for excretion. The reverse cholesterol transport pathway is indicated by arrows (net transfer of cholesterol from cells ➙ HDL ➙ LDL ➙ liver). CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FC, free cholesterol; HDL-E, HDL with apolipoprotein E; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptor; PL, phospholipid; SR-BI, class B, type I scavenger receptor; Tg, triglyceride; VLDL, very-low-density lipoprotein.
- Several steps in the metabolism of HDL can contribute to the transport of cholesterol from lipid laden macrophages of atherosclerotic arteries, termed foam cells to the liver for secretion into the bile. This pathway has been termed reverse cholesterol transport and is considered as the classical protective function of HDL towards atherosclerosis.
- High-density lipoprotein (HDL) cholesterol promotes and facilitates the process of reverse cholesterol transport (RCT), whereby excess macrophage cholesterol is effluxed to HDL and ultimately returned to the liver for excretion. Efflux to nascent and mature HDL occurs via the transporters ABCA1 and ABCG1, respectively. The HDL cholesterol is returned to the liver via the hepatic receptor SR-BI or by transfer to apolipoprotein (apo) B–containing lipoproteins by the action of cholesteryl ester transfer protein (2).
- Role of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolism Dietary (exogenous) fat is absorbed into chylomicrons (CMs). In endogenous lipid synthesis, the liver synthesizes triglycerides (TGs) and cholesteryl esters (CEs) and packages them into very-low-density lipoproteins (VLDLs). The enzyme lipoprotein lipase (LPL), bound to the surface of the capillary endothelium (especially in muscle and adipose tissue), hydrolyzes TG in CMs and in VLDLs. Apolipoprotein C-II (apoC-II), found on CMs, is a required cofactor for LPL. The free fatty acids generated from TG hydrolysis are a source of energy or fat storage, and the resulting CM remnant (CMR) is released and is eventually taken up by the liver. VLDL, which contains the major structural protein apoB-100, is hydrolyzed by LPL to form intermediate-density lipoprotein (IDL). Secreted CMs contain apoAs, which are transferred with phospholipids into the high-density lipoprotein (HDL) fraction during lipolysis. Similar HDL particles (HDL 2 ) may be formed as a byproduct of the lipolysis of VLDL. Hepatic lipase, found primarily on the endothelium of the hepatic sinusoids, hydrolyses HDL 2 TG and phospholipids to form small HDL 3 particles, 2 which may be cleared by the kidney. References: Brunzell JD. Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7 th ed. New York: McGraw-Hill; 1995:1913–1932. Breslow JL. Familial disorders of high-density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7 th ed. New York: McGraw-Hill; 1995:2031–2052. Rader DJ. Lipid disorders. In: Topol EJ, ed. Textbook of Cardiovascular Medicine. Philadelphia: Lippincott-Raven; 1998:59–90.
- HDL Metabolism in CETP Deficiency Nascent high-density lipoprotein (HDL) picks up cholesterol from cells in the periphery and is then converted into cholesteryl ester (CE)–rich HDL through the action of lecithin:cholesterol acyltransferase (LCAT). In normal lipoprotein metabolism, HDL CE can be transferred to triglyceride-rich lipoproteins through the activity of plasma CE transfer protein (CETP). In subjects with a deficiency of CETP, the conversion of HDL to very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (LDL) is blocked, leading to delayed catabolism of HDL CE, with consequent marked increases in the concentrations of HDL cholesterol and apolipoprotein A-I. References: Havel RJ, Kane JP. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7 th ed. New York: McGraw-Hill; 1995:1841–1851. Breslow JL. Familial disorders of high-density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7 th ed. New York: McGraw-Hill; 1995:2031–2052.
- HDL carries many lipid and protein species, many of which have very low concentrations but are biologically very active. For example, HDL and their protein and lipid constituents help to inhibit oxidation , inflammation, activation of the endothelium, coagulation or platelet aggregation. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known what is most important.
- High-density lipoprotein exerts a number of potentially antiatherogenic effects independent of cholesterol efflux and centripetal transport, including inhibiting lipid oxidation, impairing leukocyte adhesion and monocyte activation, promoting nitric oxide (NO) production and flow-induced vasodilation, preventing endothelial cell damage and death, and inhibiting activation of platelets and the coagulation cascade.
- HDL interacts with a cell membrane protein known as SRB1 which allows the cholesterol ester to be selectively adsorbed into the liver, thereby allowing the HDL particle to return to the blood plasma where it can again absorb cholesterol from other tissues and begin the process of reverse cholesterol transport again. Increased HDL synthesis may result in increased reverse cholesterol transport (RCT) and decrease atherosclerosis.
- High-density lipoproteins (HDL) have anti-inflammatory effects, which are implicated in its anti-atherogenic properties. Effects on endothelial cells are generally well described. In vitro studies have shown that spherical HDL from human plasma, as well as discoidal reconstituted HDL containing apolipoprotein A-I (apoA-I), inhibit expression of VCAM‑1 and ICAM-1 in endothelial cells and reduce the binding of monocytes to the endothelial surface
- HDL enhances NO production by eNOS in vascular endothelium. (a) HDL causes membrane-initiated signaling, which stimulates eNOS activity. The eNOS protein is localized in cholesterol-enriched (orange circles) plasma membrane caveolae as a result of the myristoylation and palmitoylation of the protein. Binding of HDL to SR-BI via apoAI causes rapid activation of the nonreceptor tyrosine kinase src, leading to PI3K activation and downstream activation of Akt kinase and MAPK. Akt enhances eNOS activity by phosphorylation, and independent MAPK-mediated processes are additionally required. HDL also causes an increase in intracellular Ca2+ concentration (intracellular Ca2+ store shown in blue; Ca2+ channel shown in pink), which enhances binding of calmodulin (CM) to eNOS. HDL-induced signaling is mediated at least partially by the HDL-associated lysophospholipids SPC, S1P, and LSF acting through the G protein–coupled lysophospholipid receptor S1P3. HDL-associated estradiol (E2) may also activate signaling by binding to plasma membrane–associated estrogen receptors (ERs), which are also G protein coupled. It remains to be determined if signaling events are also directly mediated by SR-BI Reference Yuhanna, IS, et al. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat. Med. 2001. 7: 853-857. Nofer, J-R, et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J. Clin. Invest. 2004. 113: 569-581. Gong, M, et al. HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. J. Clin. Invest. 2003.
- HDL regulates eNOS abundance and subcellular distribution. In addition to modulating the acute response, the activation of the PI3K–Akt kinase pathway and MAPK by HDL upregulates eNOS expression (open arrows). HDL also regulates the lipid environment in caveolae (dashed arrows). Oxidized LDL (OxLDL) can serve as a cholesterol acceptor (orange circles), thereby disrupting caveolae and eNOS function. However, in the presence of OxLDL, HDL maintains the total cholesterol content of caveolae by the provision of cholesterol ester (blue circles), resulting in preservation of the eNOS signaling module Reference Ramet, ME, et al. High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life. J. Am. Coll. Cardiol. 2003. 41: 2288-2297. Blair, A, Shaul, PW, Yuhanna, IS, Conrad, PA, Smart, EJ. Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J. Biol. Chem. 1999. 274: 32512-32519. Uittenbogaard, A, Shaul, PW, Yuhanna, IS, Blair, A, Smart, EJ. High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. J. Biol. Chem. 2000. 275: 11278-11283.
- HDL prevent formation of foam cells Perhaps the best-known function of HDL is the promotion of cholesterol efflux from cells. Efflux of cholesterol from foam cells leads to a reduction in foam cell formation; although the macrophages may accumulate, they are not converted into foam cells. As a result, the inflammatory process is arrested to a certain extent. Therefore, HDL is anti-inflammatory and also protects against the development of atherosclerosis. Reference: Miyazaki A, Rahim AT, Ohta T, Morino Y, Horiuchi S. High density lipoprotein mediates selective reduction in cholesteryl esters from macrophage foam cells. Biochim Biophys Acta 1992;1126:73-80.
- Inhibition of adhesion molecules The cytokine-induced expression of adhesion molecules in endothelial cells has been shown in vitro and more recently in vivo to be inhibited by HDL, in a process that potentially blocks a very early inflammatory stage in the development of atherosclerosis. Reference: Cockerill GW, Rye K-A, Gamble JR, Vadas MA, Barter PJ. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
- HDL inhibit the oxidative modification of LDL HDL has protective effects in addition to promoting cholesterol efflux. One of the best known of these is the ability to inhibit the oxidation of LDL. To the extent that LDL oxidation is an important step in the development of the inflammatory process, this property of HDL is clearly anti-inflammatory. Reference: Mackness MI, Abbott C, Arrol S, Durrington PN. The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J 1993;294:829-834.
- Additional anti-inflammatory properties of HDL In addition to HDL's cholesterol efflux properties, antioxidant properties, and ability to inhibit adhesion molecule expression in endothelial cells, over the last 10 to 15 years HDL has been shown to have many other effects, several of which are potentially anti-inflammatory. HDL can bind and neutralize the proinflammatory lipopolysaccharides, and may also neutralize the effects of the acute phase reactant SAA, which when it is released into the blood is transported predominantly bound to HDL. References: Baumberger C, Ulevitch RJ, Dayer JM. Modulation of endotoxic activity of lipopolysaccharide by high-density lipoprotein. Pathobiology 1991;59:378-383. Benditt EP, Eriksen N. Amyloid protein SAA is associated with high density lipoprotein from human serum. Proc Natl Acad Sci U S A 1977;74:4025-4028.
- http://www.med.umich.edu/mdrtc/cores/ChemCore/lipids.htm Lipid Measurement Fact Sheet
- HDL-C Is a Modifier of Risk at All Levels of LDL-C: the Framingham Study. Though 34% of patients with premature heart disease have LDL-C levels greater than 160 mg/dL, over half of patients (57%) with premature heart disease have low HDL-C levels. 1 The Framingham heart study demonstrated that there was a statistically significant increase in the number of cardiovascular (CV) events in patients with low HDL-C (<34 mg/dL), especially in women ( P <.01). 2,3 As HDL-C decreases, it contributes significantly to CHD risk at all levels of LDL-C. 4 As shown in the patient scenarios on the left side of slide, if all patients have near optimal levels of LDL-C (100 mg/dL), the lower the HDL-C level, the higher the risk of CHD. Also note that in a patient with an LDL-C of 220 mg/dL and an HDL-C level of 45 mg/dL, the risk of CHD is equivalent (1.2) compared with a patient with optimal LDL-C and low HDL-C (1.2). Although these findings raise the possibility that interventions that increase HDL-C might lead to a decrease in the risk of developing CHD, other studies have demonstrated that high HDL-C does not preclude the risk of developing CHD if LDL-C remains elevated. References 1. Genest JJ, et al. Am J Cardiol. 1991;67:1185-1189. 2. Kannel WB, et al. Am J Cardiol. 1983;52:9B-12B. 3. Wilson PWF, et al. Circulation. 1998;97:1837-1847. 4. Castelli WP. Can J Cardiol . 1988;4(suppl A):5A-10A.
- Analyses have also showed that HDL cholesterol is independently associated with risk for cardiovascular events in statin-treated patients independent of LDL cholesterol levels (Fig 4). Furthermore, the increase in HDL cholesterol associated with simvastatin treatment in the 4S study was predictive of benefit independent of the reduction in LDL cholesterol levels. A similar result was observed in the Lipid Research Clinics Primary Prevention Trial in which cholestyramine was used as the active agent. In this study a reduction in CHD events correlated positively with changes in LDL cholesterol levels and negatively with changes in HDL cholesterol. For every 1% increase in the concentration of HDL cholesterol there was a 0.6% reduction in CHD events that was independent of the changes in LDL cholesterol levels. References 1. Barter P, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301-10. 2. Pedersen TR, Olsson AG, Faergeman O et al . Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453-60. 3. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-64.
- Source: 1. Jocelyne R. Benatar, Ralph A. Stewar, New Zealand Medical Journal , Vol. 120, No. 2261, Sept. 7, 2007 2. Chapman M, Assmann G, Fruchart J, Shepherd J, Sirtori C. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid - a position paper developed by the European Consensus Panel on HDL-C . Cur Med Res Opin. 2004 Aug;20(8):1253-68.
- King A.C et al. Circulation.1995;91:2596-2604.
- Couillard et al . Arteriscler Thromb Vasc Biol.2004;21:1226-1232.
- Maeda K et al. Prev Med.2003;37:283-290.
- HDL inhibit endothelial cell sphingosine kinase The sphingomyelin pathway has been shown to be involved in the mechanism by which TNF-α stimulates the expression of adhesion molecules in endothelial cells. TNF-α activates sphingomyelinase, which begins the sphingomyelin pathway through ceramide, sphingosine, sphingosine 1-phosphate, and then to the nuclear transcription factor NK-κB and ultimately to the expression of a variety of adhesion proteins. In a recently reported study, HDL has been shown to inhibit sphingosine kinase, which catalyzes the sphingosine-to–sphingosine 1-phosphate step. This is at least one of the mechanisms by which HDL inhibits adhesion molecule expression. Reference: Xia P, Vadas MA, Rye KA, Barter PJ, Gamble JR. High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway: a possible mechanism for protection against atherosclerosis by HDL. J Biol Chem 1999;274:33143-33147.
- A number of long-term clinical endpoint studies 1 with statins have demonstrated conclusively that lowering serum cholesterol is associated with significant reductions in cardiovascular morbidity and mortality, both in subjects with established CHD (eg, 4S, 2 CARE, 3 LIPID, 4 ) and in individuals at risk for cardiovascular disease (CVD) (eg, WOSCOPS, 5 AFCAPS/TexCAPS, 6 HPS, 5 ASCOT-LLA 7 ). In the large statin trials, there is an approximate linear relation between CHD event rates and the LDL-C levels on treatment with either statin or placebo. The lowest event rate is in the CARE pravastatin group, which achieved a mean LDL-C of less than 95 mg/dL (2.5 mmol/L). 3 This supports the NCEP recommendation for an LDL-C target of less than 100 mg/dL (2.6 mmol/L) in secondary prevention. 8 1 Kastelein JP. Atherosclerosis. 1999;143(suppl 1):S17-S21. 2 4S Group . Lancet . 1994;344:1383-1389. 3 Sacks FM, et al. Circulation. 1998;97:1446-1452. 4 LIPID Group. N Engl J Med . 1998;339:1349-1357. 5 WOSCOPS Group. Circulation . 1998;97:1440-1445. 6 Downs JR, et al. JAMA . 1998;279:1615-1622. 7 Sever PS, et al. Lancet . 2003;361:1149-1158. 8 NCEP Expert Panel. JAMA. 2001;285:2486-2497.
- In the 1990s, the WOSCOPS, 1 AFCAPS/TexCAPS, 2 4S, 3 CARE, 4 and LIPID 5 studies demonstrated that long-term intervention with statin therapy reduces mortality and recurrent ischemic cardiovascular events both in individuals at risk for CVD and patients with stable CHD. Since this time, several trials have illustrated the benefits of statin therapy in a variety of other patient populations. The MIRACL study 6 was a 16-week, multicenter, randomized, double-blind, placebo-controlled trial that showed that intensive lowering of LDL-C with atorvastatin (80 mg/day), initiated 24-96 hours after an ACS, reduced the composite endpoint of death, nonfatal myocardial infarction (MI), resuscitated cardiac arrest, or recurrent symptomatic MI requiring emergency rehospitalization from 17.4% to 14.8% ( P = .048) within 16 weeks of treatment. HPS 7 demonstrated that, regardless of baseline LDL-C, simvastatin 40 mg/day significantly decreased the relative risk of major vascular events by 24% among patients considered to be at substantial 5-year risk of death from CHD, including patients with established CHD (primary prevention) and patients with diabetes or treated for hypertension (secondary prevention) . Moreover, there was n o lower LDL-C limit at which benefits of statin therapy were not observed. ASCOT-LLA 8 showed atorvastatin 10 mg significantly lowered the primary endpoint of nonfatal MI (including silent MI) and fatal CHD by 36% in a population of hypertensive patients who were only at moderate cardiovascular risk, and who would not conventionally be deemed dyslipidemic. The reductions in major cardiovascular events with atorvastatin emerged earlier than in many other statin trials. 1 WOSCOPS Group. Circulation . 1998;97:1440-1445. 2 Downs JR, et al. JAMA . 1998;279:1615-1622. 3 4S Group. Lancet . 1994;344:1383-1389. 4 Sacks FM, et al. Circulation . 1998;97:1446-1452. 5 LIPID Group. N Engl J Med . 1998;339:1349-1357. 6 Schwartz GG, et al. JAMA . 2001;285:1711-1718. 7 Heart Protection Study Collaborative Group. Lancet . 2002 ;360:7-22 . 8 Sever PS, et al. Lancet . 2003;361:1149-1158.
- The “ landmark ” statin trials, including CARE, 1 LIPID, 2 4S, 3 AFCAPS/TexCAPS 4 , and WOSCOPS 5 , have shown that effective lipid-lowering therapy significantly decreases morbidity and mortality from cardiovascular disease across a broad range of patients. In addition to the reduction in CHD events shown in patients with stable coronary disease, the MIRACL trial 6 demonstrated that intensive lowering of LDL-C with atorvastatin (80 mg/day), initiated 24-96 hours after an ACS, reduced the composite endpoint of death, nonfatal MI, resuscitated cardiac arrest, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization, from 17.4% to 14.8% ( P = .048). Recent data from the HPS 7 and ASCOT-LLA 8 suggest that lowering LDL-C has beneficial effects in patients with normal or moderately elevated LDL-C, and reduces the risk of major coronary events. Data from these studies indicate that all patients at high risk of CHD, including hypertensives, 8 should be considered for statin therapy, regardless of baseline LDL-C concentrations. 1 Sacks FM, et al. Circulation. 1998;97:1446-1452. 2 LIPID Group. N Engl J Med . 1998;339:1349-1357. 3 4S Group . Lancet . 1994;344:1383-1389. 4 Downs JR, et al. JAMA . 1998;279:1615-1622. 5 WOSCOPS Group. Circulation. 1998;97:1440-1445. 6 Schwartz GG, et al. JAMA. 2001;285:1711-1718. 7 Heart Protection Study Collaborative Group. Lancet. 2002 ;360:7-22 . 8 Sever PS, et al. Lancet . 2003;361:1149-1158.
- This table summarizes the ability of all major lipid-lowering drug classes to impact LDL-C, HDL-C, and triglycerides. Statins clearly dominate in terms of effectiveness at reducing TC and LDL-C. 1,2 1 NCEP Expert Panel. JAMA. 2001;285:2486-2497. 2 Jones PH et al, for the STELLAR Study Group. Am J Cardiol 2003;92:152-160.
- In the ACCESS study, treatment with atorvastatin (10 to 80 mg) yielded the highest proportion of patients reaching NCEP LDL-C goals (76.3% vs 34.2-57.9%; P <.01). 1 Andrews TC, et al. Am J Med . 2001;111:185-191.