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:- [phone]

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 the HDL 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 nanometers 12.5 nanometers
They have high density ~1.12 They have high density ~1.12
mainly because of high mainly 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 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 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

8. HDL StructureHDL Structure

9. HDL StructureHDL Structure

10. Alpha HDL BuoyancyAlpha HDL Buoyancy

11. HDL SynthesisHDL Synthesis
Synthesis of new high-density Synthesis of new high-density
lipoprotein (HDL) particles begins lipoprotein (HDL) particles begins
with the secretion of with the secretion of
apolipoprotein A-I (apo A-I) from apolipoprotein A-I (apo A-I) from
the liver. the liver.
The resulting HDL2 (larger, less The resulting HDL2 (larger, less
dense particles) and HDL3 dense 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 cholesterol HDL metabolism and reverse cholesterol
transporttransport

17. Role of Hepatic Lipase and Lipoprotein Lipase Role 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
HDL
2
PL
A-I
CE
HDL
3
PL
Phospholipids and
apolipoproteins

18. HDL Metabolism in CETP DeficiencyHDL Metabolism in CETP Deficiency
A-I
CE
FC
FC
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
P
L
,F
C
,C
E
,a
p
o
’s
P
L
,F
C
,C
E
,a
p
o
’s
Renal clearance

20. CETP Inhibition and Lipoprotein MetabolismCETP Inhibition and Lipoprotein Metabolism

21. Cholesterol efflux and reverse cholesterol Cholesterol 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
Intima
HDL 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
Mackness MI et al. Biochem J 1993;294:829-834.
Endothelium
Vessel Lumen
Monocyte
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 neutralizes HDL bind and neutralizes
proinflammatory proinflammatory
lipopolysaccharideslipopolysaccharides
The acute phase reactant The acute phase reactant
SAA binds to plasma SAA binds to plasma
HDL, which possibly HDL, which possibly
neutralizes the effects of neutralizes 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 of The American Heart Association, NIH and NCEP provides a set of
guidelines for fasting HDL levels guidelines 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, optimal High HDL level, optimal
condition considered protective condition 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
R
i
s
k

o
f

C
H
D
Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.
3
2
1
4
Equivalent Risk

37. Major cardiovascular event frequency by Major 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 exercise quality of exercise

41. HERITAGE STUDY: Effects of 20 wks of endurance exercise training HERITAGE 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 CVD The statin trials have demonstrated significant decreases in CVD
morbidity and mortality. morbidity and mortality.
•Reduction in CVD events has been demonstrated in patients Reduction 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 beneficial Additionally, 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 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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51. Statin Efficacy: ACCESSStatin Efficacy: ACCESS

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