metabolism and protective properties of hdl february 23, 2016 · 2020. 2. 13. · metabolism and...
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Metabolism and Protective Properties of HDL
February 23, 2016
Khalid Al-Rasadi, BSc, MD, FRCPC
Head of Biochemistry Department, SQU
Head of Lipid and LDL-Apheresis Unit, SQUH
President of Oman society of Lipid & Atherosclerosis (OSLA)
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DISCLOSURE
AstraZeneca
Pfizer
MSD
Abbott
Aegerion
Sanofi
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Presentation Outlines
• HDL biogenesis and metabolism
• HDL function and cardioprotective properties
• HDL dysfunction
• Functional and compositional assessment of HDL
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HDL biogenesis and metabolism
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Structure of HDL
Surface monolayer ofphospholipidsand free cholesterol
Hydrophobic core of triglycerideand cholesteryl esters
apoA-I
apoA-II
Note: LFA1 denotes Lipid Free Apo Lipoprotein A1r HDL denotes Reconstituted HDL
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HDL Consists of Heterogeneous
Particles, but Their Clinical Relevance
Remains to Be Established
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HDL are Heterogenes (Contents)
PhospholipidsTriglycerids
Esterified cholesterol
Apo A1Free cholesterol
> 1000 different lipids(Phospholipid species, Cholesterol Ester, Trigylcerides, …)
70 different proteins(ApoA1, PON-1, ApoA2, ApoCIII,
ApoE, ApoH, ….)
CholesterolEster
PON-1
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0
10
20
30
sn-2 Fatty Acid
sn-1 Fatty Acid
% O
ccu
rren
ce
16:0
PL
PO
PA
16:0
18:1
18:2
20:3
20:4
20:5
22:6
18:0
18:1
18:2
20:3
20:4
20:5
SL
18:2
18:1
18:2
20:4
20:5
18:1
18:2
Phospholipid Composition
PD
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Discoidal
Spherical
Globular
Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.
HDL are Heterogeneous(Particle Shape)
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HDL are Heterogeneous
(Surface Charge and Mobility)
Origin -Migration-Migration Pre--Migration
(E)HDL
Lipid-poor/Lipid-free apoA-I
Discoidal HDL
(A-I)HDL
(A-I/A-II)HDL
+Anode
-Cathode
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HDL2aHDL2b HDL3cHDL3bHDL3a
HDL Particle Size/Electrophoretic Mobility
Apolipoprotein ContentParticle Shape
Discoidal
Spherical
A-I HDL A-I/A-II HDL
Lipid-poor apoA-I
HDL Subpopulations
+other apos: A-IV, C, D, E, etc.
+non-apo proteins: inflam, thromb, etc.
--------------------------Alpha-migrating---------------------------Pre-beta-migrating--
Globular Discoidal
Globular
Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.
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The HDL heterogeneity is the result of activity of several factors that
assemble and remodel HDL in plasma
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apoA-I
(lipid-free)
Origin of ApoA-1
Chylomicrons
Lipolysis
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Factors that assemble and remodel HDL in plasma
• ATP-binding cassette transporter (ABCA1)
• Lecithin—cholesterol acyltransferase (LCAT)
• Cholesteryl Ester Transfer Protein (CETP)
• Hepatic Lipase (HL)
• Phospholipid Transfer Protein (PLTP)
• Scavenger receptor class B type I (SR-B1)
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Generates discoidal HDL by effluxing
phospholipids and cholesterol from cell
membranes to lipid-free/lipid-poor apoA-I
ABCA1
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NC
Lipid-free/lipid-poor apoA-I
Discoidal HDL
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• Generates most of the cholesteryl esters in plasma
•Activated by apoA-I and, to a lesser extent,
apoE and apoA-IV
•ApoA-II does not activate LCAT
• Remodels discoidal HDL into spherical HDL
LCAT
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Spherical (A-I)HDL
UC
LCAT
Lyso-PCPC
LCAT Converts Discoidal HDL into Spherical HDL
Discoidal HDL
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Spherical (A-I)HDL
UC
LCAT
Lyso-PCPC
LCAT Converts Discoidal HDL into Spherical HDL
Discoidal HDL
UC(concentration
gradient)
Peripheral cells
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• Generates most of the cholesteryl esters in plasma
•Activated by apoA-I and, to a lesser extent,
apoE and apoA-IV
•ApoA-II does not activate LCAT
• Remodels discoidal HDL into spherical HDL
LCAT
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Discoidal (A-I)HDL Discoidal (A-II)HDL
LCAT/LDL
Spherical (A-I/A-II)HDLClay et al. J. Biol Chem. 2000 275:9019-9025
Formation of (A-I/A-II)HDL by LCAT
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• Transfers core lipids between HDL, VLDL and LDL
• Remodels HDL into large and small particles
• Mediates the dissociation of apoA-I from HDL
CETP
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Barter et al; Biochem J. 1982; 2081:1, Swenson et al. J. Biol. Chem. 1988;263:5150, Tall. J. Lipid res. 1993; 34:1255
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Role of CETP in plasma cholesterol transport
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• Hydrolyses HDL phospholipids and triglycerides
• Remodelling is enhanced by CETP
• Mediates the dissociation of apoA-I from HDL
• Remodels HDL into small particles
Hepatic Lipase
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TGCE
VLDL
Large Spherical HDLCE
TG
CETP
Lipid-free
apoA-I
HL
Small Spherical HDL
TGCE
CETG
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•Transfers phospholipids between HDL and VLDL
•Remodels HDL into large and small particles
•Mediates the dissociation of apoA-I from HDL
PLTP
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Scavenger receptor type B1 ( SRB1)
• SRB1 promotes the selective hepatic uptake of HDL cholesteryl esters
• SRB1 thus also remodels HDL
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HDL function and cardioprotective properties
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39
39
Mechanisms of Cellular Cholesterol Effluxto HDL particles
Extracellular space Cell membrane
FC
FC
FC
FC
ABCA1
Diffusion
SR-B1
Diffusion
SR-B1ABCG1
Diffusion
SR-B1ABCG1
Lipid-poor ApoA-I
Discoidal HDL
Small spherical HDL
Larger spherical HDL
LCAT
LCAT
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40
Current Model of HDL-C Metabolism: Reverse Cholesterol Transport
BCE
Bile
SR-BILDLReceptor
Liver
FCCE LCAT
A-1
A-1
CEHL, EL
Macrophage
Mature HDL-C
Cuchel M et al. ATVB. 2003;23:1710–1712; Assmann G et al. Circulation. 2004;109(23 suppl 1):III-8–III-14.
FC
Nascent HDL
CE
TP
VLDL/LDL-C
Net transfer of cholesterol
FC
SR-BI
ABCG1
CE
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Potential Antiatherogenic Actions of HDL
MCP-1 = monocyte chemoattractant protein-1
Adapted from Barter PJ et al. Circ Res. 2004;95:764-772.
Monocyte
Macrophage
Foam
cell
Vessel Lumen
Endothelium
IntimaCytokines
Adhesion
molecule
Oxidized LDL
LDL
LDL
HDL inhibits expression of endothelial cell adhesion
molecules and MCP-1
MCP-1
HDL inhibits
oxidation of LDL-C
HDL promotes efflux of
cholesterol from foam cells
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Drew et al. Circulation 2009;119:2103-2111
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ABCA1 RPKA
RPKA
PKA
PKA
R
R cAMP
cAMP
Lipid-free apoA-I
Ca2+
Ca2+Ca2+
Ca2+
InsulinAAAAA
AC AC
Adenylyl cyclase
cAMP
cAMP
cAMP
cAMP
cAMP
Insulin release
PKA
FOXO1
T24 S256
S319
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HDL dysfunction
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Functional and compositional
assessment of HDL
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HDL: New Dimensions
QUANTITYHDL-C / Apo AI
QUALITYParticle structure
Lipidome, Proteome
Functionality
Kontush A, Chapman MJ. Pharmacol Rev. 2006.
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Functional and Compositional Assessment of HDL
• Cholesterol efflux
• Antioxidant activity
• Anti-inflammatory activity
• Proteomics/lipidomics
Note: these are research tools w/o known clinical
relevance of application
Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.
Clin Chem. 2011;57(3):392-410.
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Beyond HDL-C: Laboratory assessment of reverse cholesterol efflux (by plasma)
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Study design: Endothelial effects of HDL -endothelial bioassays
Isolation of HDL2/3(by sequential ultracentrifugation)
Endothelial Function
(Endothelial cell NO production and vasoreactivity)
ESR spectroscopyOrgan chamber
ESR spectroscopy
Patients with acute coronary syndrome (n=25)Patients with stable coronary disease (n=25)
Healthy control subjects (n=25)
Vascular effects
Anti-oxidanteffects
(Endothelial cell superoxide production)
Anti-inflammatoryeffects
(Endothelial cell inflammatory activation)
Monocyte adhesion VCAM-1 expression
Effects on Re-Endothelialization
Carotid artery injury model in nude mice
Anti-thromboticeffects
Tissue factor Arterial thrombosis
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HDL Proteome
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Proposed Term Very Large HDL (HDL-VL)
Large HDL-V (HDL-L)
Medium HDL (HDL-M)
Small HDL (HDL-S)
Very Small HDL (VS-HDL)
Density range, g/mL 1.063-1.087 1.088-1.110 1.110-1.129 1.129-1.154 1.154-1.21
Size range, nm 12.9-9.7 9.7-8.8 8.8-8.2 8.2-7.8 7.8-7.2
Density gradient
ultracentrifugation HDL2b HDL2a HDL3a HDL3b HDL3c
Density range, g/mL 1.063-1.087 1.088-1.110 1.110-1.129 1.129-1.154 1.154-1.170
Gradient gel
electrophoresis HDL2b HDL2a HDL3a HDL3b HDL3c
Size range, nm 12.9-9.7 9.7-8.8 8.8-8.2 8.2-7.8 7.8-7.2
2D gel electrophoresis Alpha-1 Alpha-2 Alpha-3 Alpha-4 Preβ-1 HDL
Size range, nm 11.2-10.8 9.4-9.0 8.5-7.5 7.5-7.0 6.0-5.0
NMR Large HDL-P Medium HDL-P Small HDL-P
Size range, nm 12.9-9.7 9.7-8.8 8.8-8.2 8.2-7.8 7.8-7.2
Ion mobility HDL2b HDL2a + 3
Size range, nm 14.5-10.5 10.5-7.65
Separation of HDL by Physical Properties
Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.
Clin Chem. 2011;57(3):392-410.
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Burning questions to resolve the puzzles with HDL?
• Can we relate HDL associated function to unique HDL subpopulations?
• Can distinct function of HDL subpopulations be accounted by specific protein components?
• Which of the known HDL functions protect against CVD?
Answers to these questions require much more research
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