Focus on high density lipoproteinsPresentation Transcript
Focus on High Density LipoproteinsFocus on High Density LipoproteinsDr. Sachin Verma MD, FICM, FCCS, ICFCFellowship in Intensive Care MedicineInfection Control Fellows CourseConsultant Internal Medicine and Critical CareIvy Hospital Sector 71 MohaliWeb:- http://www.medicinedoctorinchandigarh.comMob:- +91-7508677495
Lipoprotein Classes and AtherosclerosisLipoprotein Classes and AtherosclerosisChylomicrons,Chylomicrons,VLDL, and theirVLDL, and theircatabolic remnantscatabolic remnantsLDLLDL HDLHDLPro-atherogenicPro-atherogenic Anti-atherogenicAnti-atherogenic
IntroductionIntroduction High-density lipoprotein (HDL) is one ofthe five major groups of lipoproteinsthat enables lipids like cholesterol andtriglycerides to be transported within thewater based blood stream. HDL can remove cholesterol fromatheroma within arteries and transport itback to the liver for excretion or re-utilization. Therefore HDL is also calledas good cholesterol.
Structure of HDLStructure of HDL HDL is the smallest of theHDL is the smallest of thelipoprotein 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 ~1.12mainly because of highmainly because of highproportion of proteinsproportion of proteins
HDL StructureHDL StructureHDL contains several types ofHDL contains several types ofapolipoproteins 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 areapo A-I and apo A-II.apo A-I and apo A-II.
HDL StructureHDL StructureCholesterolacceptorCholesterylesterdonorReverse CholesterolTransport (RCT)Anti-thromboticHDL-CProtection againstoxidationModulation ofendothelial functionProtection of the vessel wallEndothelial repairAnti-inflammatory
HDL StructureHDL Structure
HDL StructureHDL Structure
Alpha HDL BuoyancyAlpha HDL Buoyancy
HDL SynthesisHDL Synthesis Synthesis of new high-densitySynthesis of new high-densitylipoprotein (HDL) particles beginslipoprotein (HDL) particles beginswith the secretion ofwith the secretion ofapolipoprotein A-I (apo A-I) fromapolipoprotein A-I (apo A-I) fromthe liver.the liver. The resulting HDL2 (larger, lessThe resulting HDL2 (larger, lessdense particles) and HDL3dense particles) and HDL3(smaller, more dense particles) can(smaller, more dense particles) canserve as acceptors for ABCG1-serve as acceptors for ABCG1-mediated cholesterol efflux26.mediated cholesterol efflux26.
Role of HDL in lipid redistribuionRole of HDL in lipid redistribuionRole of high-density lipoprotein(HDL) in the redistribution oflipids from cells with excesscholesterol to cells requiringcholesterol or to the liver forexcretion. The reversecholesterol transport pathway isindicated by arrows (nettransfer of cholesterol from cellsHDL LDL liver).➙ ➙ ➙
Reverse Cholesterol Transport: Cellular levelReverse Cholesterol Transport: Cellular levelSeveral steps in the metabolismof HDL can contribute to thetransport of cholesterol fromlipid laden macrophages ofatherosclerotic arteries, termedfoam cells to the liver forsecretion into the bile. Thispathway has been termedreverse cholesterol transportand is considered as theclassical protective function ofHDL towards atherosclerosis.
Reverse Cholesterol Transport: Cellular levelReverse Cholesterol Transport: Cellular levelHigh-density lipoprotein (HDL)cholesterol promotes and facilitatesthe process of reverse cholesteroltransport (RCT), whereby excessmacrophage cholesterol is effluxed toHDL and ultimately returned to theliver for excretion. Efflux to nascentand mature HDL occurs via thetransporters ABCA1 and ABCG1,respectively. The HDL cholesterol isreturned to the liver via the hepaticreceptor SR-BI or by transfer toapolipoprotein (apo) B–containinglipoproteins by the action ofcholesteryl ester transfer protein (2).
HDL metabolism and reverse cholesterolHDL metabolism and reverse cholesteroltransporttransport
Role of Hepatic Lipase and Lipoprotein LipaseRole of Hepatic Lipase and Lipoprotein Lipasein HDL Metabolismin HDL MetabolismCM = chylomicron; CMR = chylomicron remnant; HDL =high-density lipoprotein; HL = hepatic lipase; IDL =intermediate-density lipoprotein; LPL = lipoprotein lipase;PL = phospholipase; TG = triglycerideBKidneyEndotheliumBTGCMR/IDLC-IICM/VLDLHLLPLA-ICETGHDL2PLA-ICEHDL3PLPhospholipids andapolipoproteins
HDL Metabolism in CETP DeficiencyHDL Metabolism in CETP DeficiencyA-ICEFCFCLCATA-IMacrophageBDelayed catabolismCETPABC1HDLVLDL/LDLNascent HDLCE
CETP Inhibition and Lipoprotein MetabolismCETP Inhibition and Lipoprotein Metabolism
Cholesterol efflux and reverse cholesterolCholesterol efflux and reverse cholesteroltransport is modulated by two receptorstransport is modulated by two receptors
HDL-C Protection Against AtherosclerosisHDL-C Protection Against AtherosclerosisActs by inhibitingActs by inhibiting OxidationOxidation InflammationInflammation Activation of endotheliumActivation of endothelium CoagulationCoagulation Platelet aggregationPlatelet aggregation
Inhibitory properties of HDLInhibitory properties of HDL
HDL: Apo AI-rich particlesHDL: Apo AI-rich particles
Anti-inflammatory effects of HDLAnti-inflammatory effects of HDL
Antioxidant Action of HDL cholesterolAntioxidant Action of HDL cholesterol
Antioxidant Action of HDL cholesterolAntioxidant Action of HDL cholesterol
LDLLDLMiyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.EndotheliumVessel LumenMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesHDL Prevents Formation of Foam CellsHDL Prevents Formation of Foam CellsIntimaHDL Promote Cholesterol EffluxFoamCell
LDLLDLCockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.EndotheliumVessel LumenMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesInhibition of Adhesion MoleculesInhibition of Adhesion MoleculesIntimaHDL InhibitOxidationof LDLHDL Inhibit Adhesion Molecule ExpressionFoamCellHDL Promote CholesterolEfflux
LDLLDLEndotheliumVessel LumenMonocyteModified LDLMacrophageMCP-1AdhesionMoleculesCytokinesHDL Inhibits the Oxidative Modification of LDLHDL Inhibits the Oxidative Modification of LDLFoamCellHDL Promote CholesterolEffluxIntimaHDLInhibitOxidationof LDL
Additional Anti-inflammatory Properties of HDLAdditional Anti-inflammatory Properties of HDL HDL bind and neutralizesHDL bind and neutralizesproinflammatoryproinflammatorylipopolysaccharideslipopolysaccharides The acute phase reactantThe acute phase reactantSAA binds to plasmaSAA binds to plasmaHDL, which possiblyHDL, which possiblyneutralizes the effects ofneutralizes the effects ofSAASAA1. 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
Apo A-I protects against atherosclerosisApo A-I protects against atherosclerosis
Recommended range of HDLRecommended range of HDLThe American Heart Association, NIH and NCEP provides a set ofThe American Heart Association, NIH and NCEP provides a set ofguidelines for fasting HDL levelsguidelines for fasting HDL levelsLevel mg/dLLevel mg/dL Level mmol/LLevel mmol/L InterpretationInterpretation<40 for men, <50 for<40 for men, <50 forwomenwomen<1.03<1.03 Low HDL cholesterol,Low HDL cholesterol,heightened risk for heart diseaseheightened risk for heart disease40–5940–59 1.03–1.551.03–1.55 Medium HDL levelMedium HDL level>60>60 >1.55>1.55 High HDL level, optimalHigh HDL level, optimalcondition considered protectivecondition considered protectiveagainst heart diseaseagainst heart disease
Relationship between HDL cholesterol and CHD events.Relationship between HDL cholesterol and CHD events.Data from the Framingham StudyData from the Framingham StudyRiskofCHDCastelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.3214Equivalent Risk
Major cardiovascular event frequency byMajor cardiovascular event frequency byLDL-C and HDL-C levels in TNT studyLDL-C and HDL-C levels in TNT study
Statin Evidence: BenefitsStatin Evidence: Benefits• The statin trials have demonstrated significant decreases in CVDThe statin trials have demonstrated significant decreases in CVDmorbidity and mortality.morbidity and mortality.• Reduction in CVD events has been demonstrated in patientsReduction in CVD events has been demonstrated in patientswith 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 beneficialeffects in patients with normal or moderately elevated LDL-C.effects in patients with normal or moderately elevated LDL-C.
Drug ClassDrug Class LDL-CLDL-C HDL-CHDL-C TriglyceridesTriglyceridesStatins*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 orSequestrantsSequestrants increaseincreaseNicotinic 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 LoweringAdapted from NCEP Expert Panel. JAMA. 2001;285:2486-2497.vvvvvvvvvvv
Statin Efficacy: ACCESSStatin Efficacy: ACCESS
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