Focus on high density lipoproteins

Focus on High Density LipoproteinsFocus on High Density Lipoproteins

Dr. Sachin Verma MD, FICM, FCCS, ICFCFellowship in Intensive Care Medicine

Infection Control Fellows Course Consultant Internal Medicine and Critical Care

Ivy Hospital Sector 71 MohaliWeb:- http://www.medicinedoctorinchandigarh.com

Mob:- +91-7508677495

Lipoprotein Classes and AtherosclerosisLipoprotein Classes and Atherosclerosis

Chylomicrons,Chylomicrons,VLDL, and theirVLDL, and theircatabolic remnantscatabolic remnants

LDLLDL HDLHDL

Pro-atherogenicPro-atherogenic Anti-atherogenicAnti-atherogenic

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.

Structure of HDLStructure of HDL

HDL is the smallest of the HDL is the smallest of the lipoprotein particles.lipoprotein particles.

HDL particles have a size of HDL particles have a size of 6-12.5 nanometers 6-12.5 nanometers

They have high density They have high density ~1.12 mainly because of ~1.12 mainly because of high proportion of proteinshigh proportion of proteins

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.


HDL contains several types of HDL 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 Their most abundant apolipoproteins areare

apo A-I and apo A-II.apo A-I and apo A-II.


Cholesterolacceptor

Cholesterylesterdonor

Reverse Cholesterol Transport (RCT)

Anti-thromboticHDL-C

Protection against oxidation

Modulation ofendothelial function

Protection of the vessel wall

Endothelial repair

Anti-inflammatory

Alpha HDL BuoyancyAlpha HDL Buoyancy

HDL SynthesisHDL Synthesis

Synthesis of new high-density Synthesis of new high-density lipoprotein (HDL) particles lipoprotein (HDL) particles begins with the secretion of begins with the secretion of apolipoprotein A-I (apo A-I) apolipoprotein A-I (apo A-I) from the liver. from the liver.

The resulting HDL2 (larger, The resulting HDL2 (larger, less dense particles) and less dense particles) and HDL3 (smaller, more dense HDL3 (smaller, more dense particles) can serve as particles) can serve as acceptors for ABCG1-mediated acceptors for ABCG1-mediated cholesterol efflux26. cholesterol efflux26.

Reverse Cholesterol Transport: Cellular levelReverse Cholesterol Transport: Cellular level

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). ➙


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).

HDL metabolism and reverse HDL metabolism and reverse cholesterol transportcholesterol transport

Role of Hepatic Lipase and Role of Hepatic Lipase and Lipoprotein Lipase in HDL Lipoprotein Lipase in HDL MetabolismMetabolism

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

EndotheliumB

TG

CMR/IDL

C-II

CM/VLDL

HL

LPL

A-I

CE TG

HDL2

PL

A-I

CE

HDL3

PL

Phospholipids and

apolipoproteins

HDL Metabolism in CETP DeficiencyHDL Metabolism in CETP Deficiency

A-I

CEFCFC

LCAT

A-I

Macrophage

B

Delayed catabolism

CETP

ABC1

HDL

VLDL/LDL

Nascent HDL

CE

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 lipidationmaturation

- ABCA1- ABCG1- LCAT

HDL remodeling

- HL, EL, PLTP?

- apoCI?

- CETP

PL,F

C,C

E,a

po’s

PL,F

C,C

E,a

po’s

Renal clearance

CETP Inhibition and Lipoprotein CETP Inhibition and Lipoprotein MetabolismMetabolism

Cholesterol efflux and reverse Cholesterol efflux and reverse cholesterol transport is modulated by cholesterol transport is modulated by two receptorstwo receptors

HDL-C Protection Against HDL-C Protection Against AtherosclerosisAtherosclerosis

Acts by inhibitingActs by inhibiting

OxidationOxidation InflammationInflammation Activation of Activation of

endotheliumendothelium CoagulationCoagulation Platelet aggregationPlatelet aggregation

Inhibitory properties of HDLInhibitory properties of HDL

HDL-C: Anti-atherogenic effectsHDL-C: Anti-atherogenic effects

HDL inhibits expression of adhesion molecules

HDL inhibitsoxidation

of LDL

HDL promotes cholesterol

efflux

HDL activates

eNOS

LDL

LDL

Endothelium

Vessel Lumen

Monocyte

Modified LDL

Macrophage

MCP-1

AdhesionMolecules

Cytokines

Intima

Foam Cell

NO

NO

NO

NO

RCT

HDL metabolism: 5 key genesHDL metabolism: 5 key genes

HDL: Apo AI-rich HDL: Apo AI-rich particlesparticles

Anti-inflammatory effects of HDLAnti-inflammatory effects of HDL

Antioxidant Action of HDL cholesterolAntioxidant Action of HDL cholesterol

Antioxidant Action of HDL Antioxidant Action of HDL cholesterolcholesterol

LDL

LDL

Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.

Endothelium

Vessel LumenMonocyte

Modified LDL

Macrophage

MCP-1AdhesionMolecules

Cytokines

HDL Prevents Formation of Foam HDL Prevents Formation of Foam CellsCells

IntimaHDL Promote Cholesterol Efflux

Foam Cell

LDL

LDL

Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.

Endothelium


Modified LDL

Macrophage


Cytokines

Inhibition of Adhesion MoleculesInhibition of Adhesion Molecules

Intima

HDL InhibitOxidation

of LDL

HDL Inhibit Adhesion Molecule Expression

Foam Cell

HDL Promote Cholesterol Efflux

LDL

LDL

Mackness MI et al. Biochem J 1993;294:829-834.

Endothelium


Modified LDL

Macrophage


Cytokines

HDL Inhibits the Oxidative Modification HDL Inhibits the Oxidative Modification of LDLof LDL

Foam Cell

HDL Promote Cholesterol Efflux

Intima

HDL Inhibit

Oxidationof LDL

Additional Anti-inflammatory Properties Additional Anti-inflammatory Properties of HDLof HDL

HDL bind and HDL bind and neutralizes neutralizes proinflammatory proinflammatory lipopolysaccharideslipopolysaccharides

The acute phase The acute phase reactant SAA binds to reactant SAA binds to plasma HDL, which plasma HDL, which possibly neutralizes possibly neutralizes the effects of SAAthe effects of SAA

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

Apo A-I protects against atherosclerosisApo A-I protects against atherosclerosis

Recommended range of HDLRecommended range of HDL

The American Heart Association, NIH and NCEP provides a The American Heart Association, NIH and NCEP provides a set of guidelines for fasting HDL levels set of guidelines for fasting HDL levels

Level mg/dLLevel mg/dL Level mmol/LLevel mmol/L InterpretationInterpretation

<40 for men, <50 <40 for men, <50 for womenfor women

<1.03<1.03 Low HDL cholesterol, Low HDL cholesterol, heightened risk for heart heightened risk for heart diseasedisease

40–5940–59 1.03–1.551.03–1.55 Medium HDL levelMedium HDL level

>60>60 >1.55>1.55 High HDL level, optimal High HDL level, optimal condition considered condition considered protective against heart protective against heart diseasedisease

Relationship between HDL cholesterol and CHD events. Relationship between HDL cholesterol and CHD events. Data from the Framingham StudyData from the Framingham Study

Ris

k o

f C

HD

Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.

3

2

1

4Equivalent Risk

Major cardiovascular event Major cardiovascular event frequency by LDL-C and HDL-C frequency by LDL-C and HDL-C levels in TNT studylevels in TNT study

Causes of Low HDLCauses of Low HDL

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

HDL-C levels are modifiable by the quantity andHDL-C levels are modifiable by the quantity and quality of exercise quality of exercise

HERITAGE STUDY: Effects of 20 wks of endurance HERITAGE STUDY: Effects of 20 wks of endurance

exercise training on lipid profileexercise training on lipid profile

Smoking cessation increases only HDL-C, but not Smoking cessation increases only HDL-C, but not TC,LDL-C or TGTC,LDL-C or TG

Mechanism of action of nicotinic acidMechanism of action of nicotinic acid

Fenofibrate & gemfibrozil are derivatives of fibric acid that lower TGs and increase HDL levels. Fenofibrate is more effective at lowering LDL & TGs.

FibratesFibrates

Mechanism of Action of FenofibrateMechanism of Action of Fenofibrate

Statin drugs are structural analogs of Statin drugs are structural analogs of HMG-CoAHMG-CoA

Statin Evidence: Landmark Statin TrialsStatin Evidence: Landmark Statin Trials

Statin Evidence: Expanding BenefitsStatin Evidence: Expanding Benefits

Statin Evidence: BenefitsStatin Evidence: Benefits

• The statin trials have demonstrated significant The statin trials have demonstrated significant

decreases in CVD morbidity and mortality. decreases in CVD morbidity and mortality.

• Reduction in CVD events has been demonstrated in Reduction in CVD events has been demonstrated in

patients with stable CHD as well as acute coronary patients with stable CHD as well as acute coronary

syndrome patients.syndrome patients.

• Additionally, lowering LDL-C to target levels has Additionally, lowering LDL-C to target levels has

beneficial effects in patients with normal or moderately beneficial effects in patients with normal or moderately

elevated LDL-C.elevated LDL-C.

Drug ClassDrug Class LDL-CLDL-C HDL-CHDL-C Triglycerides Triglycerides

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.

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v

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Statin Efficacy: ACCESSStatin Efficacy: ACCESS

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Focus on high density lipoproteins

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