lipid/lipoprotein structure and metabolism (overview)€¦ · lipid/lipoprotein structure and...
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Lipid/Lipoprotein Structure and Metabolism (Overview)
Philip BarterInternational Atherosclerosis Society
Centre for Vascular ResearchUniversity of New South Wales
Sydney, Australia
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Received honorariums for participating as a consultant or as a member of advisory boards for AMGEN, AstraZeneca, CSL-Behring, Lilly, Merck, Novartis, Pfizer and Roche and for giving lectures for AMGEN, AstraZeneca, Merck and Pfizer.
Disclosures
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Atherosclerotic Cardiovascular disease
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Atherosclerotic Cardiovascular disease
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Clinical manifestations of Atherosclerotic Cardiovascular Disease (ASCVD)
• Coronary artery: Myocardial infarction
• Carotid artery: Stroke
• Mesenteric artery: Intestinal gangrene
• Other arteries: Peripheral arterial disease
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Modifiable Risk Factors for Atherosclerotic Cardiovascular disease (ASCVD)
• Smoking• Elevated low density lipoproteins (LDLs)• Elevated triglyceride-rich lipoproteins• Reduced high density lipoproteins (HDLs)• Elevated blood pressure• Diabetes• Abdominal obesity
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Modifiable Risk Factors for Atherosclerotic Cardiovascular disease (ASCVD)
• Smoking• Elevated low density lipoproteins (LDLs)• Elevated triglyceride-rich lipoproteins• Reduced high density lipoproteins (HDLs)• Elevated blood pressure• Diabetes• Abdominal obesity
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Plasma lipoproteins
•Why do we have plasma lipoproteins?
•What are plasma lipoproteins?
•What is the metabolism of plasma lipoproteins?
•What is the relationship of plasma lipoproteins to atherosclerosis?
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Plasma lipoproteins
•Why do we have plasma lipoproteins?
•What are plasma lipoproteins?
•What is the metabolism of plasma lipoproteins?
•What is the relationship of plasma lipoproteins to atherosclerosis?
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Why do we have plasma lipoproteins?
• Main reason for having plasma lipoproteins is to transport triglyceride and cholesterol through plasma between tissues
• Plasma is mainly water and cholesterol and triglyceride are not water-soluble
• Incorporation of cholesterol and triglyceride into lipoproteins allows them to be transported in plasma
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Why do we have plasma lipoproteins?
Several other functions of plasma lipoproteins will be covered in other lectures
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Plasma lipoproteins
•Why do we have plasma lipoproteins?
•What are plasma lipoproteins?
•What is the metabolism of plasma lipoproteins?
•What is the relationship of plasma lipoproteins to atherosclerosis?
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Surface monolayer ofphospholipidsand free cholesterol
Hydrophobic core of triglycerideand cholesteryl esters
apolipoproteins
Structure of plasma lipoproteins
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Lipoprotein fractions in plasma
Chylomicrons,VLDLs, and theircatabolic remnants
LDLs HDLs
Pro-atherogenic Anti-atherogenic
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Chylomicrons
• Formed in intestinal cells
• Function to transport dietary triglyceride and cholesterol to tissues in the body
• Main core lipid is triglyceride
• Main protein is apoB-48
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Very low density lipoproteins (VLDLs)
• Formed in the liver
• Function to transport triglyceride and cholesterol from the liver to tissues in the body
• Main core lipids is triglycerides
• Main protein is apoB-100
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Low density lipoproteins (LDLs)
• Formed as end-products of the catabolism of VLDLs
• Function to transport cholesterol from plasma to tissues in the body
• Main core lipids are cholesteryl esters
• Main protein is apoB-100
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High density lipoproteins (HDLs)
• Assembled within the plasma from several constituents
• Function to transport intracellular cholesterol into the plasma
• Main core lipids are cholesteryl esters
• Main proteins are apoA-I and apoA-II
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Plasma lipoproteins
•Why do we have plasma lipoproteins?
•What are plasma lipoproteins?
•What is the metabolism of plasma
lipoproteins?
•What is the relationship of plasma lipoproteins to atherosclerosis?
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Plasma lipid transport:Exogenous pathway
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Formation of chylomicrons
Free cholesterol(FC)
CE
FC
CE
Intestinal cell
Chylomicron
Intestinal lumenFree fatty acid(FFA)
FFA
TG
TG Lymph(thoracic duct)
Blood
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Metabolism of chylomicrons
CE
Chylomicron
TG FFALPL
Adipose andother tissues
CE TG
Chylomicron remnantCEHDL
CETP
Liver
Intestine
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Plasma lipid transport:Endogenous pathway
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LiverCETG
FC
Adiposetissue
FFA
Endogenous pathway
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Liver VLDL
CE
CETGTGFC
Adiposetissue
FFA
Endogenous pathway
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LiverCE
CETGTG LPLFC
Adipose andother tissues
Adiposetissue
FFA
FFA
VLDL
Endogenous pathway
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LiverCE
CE
CE
LDL
TGTG LPLFC
TG
Adipose andother tissues
Adiposetissue
FFA
FFA
VLDL
Endogenous pathway
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LiverCE
CE
CE
LDL
TGTG LPLFC
TG
Adipose andother tissues
LiverLDL receptor
Adiposetissue
FFA
FFA
VLDL
Endogenous pathway
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Liver
CE
CE
CE
CE
LDL
TGTG
LDL receptor
LPLFC
TG
Adipose andother tissues
LiverLDL receptor
Adiposetissue
FFA
FFA
Cell inperipheral tissue
VLDL
Endogenous pathway
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Liver
FC
CE
CE
CE
CE
LDL
TGTG
LDL receptor
LPLFC
TG
Adipose andother tissues
LiverLDL receptor
Adiposetissue
FFA
FFA
Newsynthesis
Cell inperipheral tissue
VLDL
Endogenous pathway
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Liver
FC
CE
CE
CE
CE
CE
LDL
HDL
TGTG
LDL receptor
LPLFC
TG
Adipose andother tissues
TG
LiverLDL receptor
Adiposetissue
FFA
FFA
Newsynthesis
Cell inperipheral tissue
VLDL
LCAT ABCA1
Endogenous pathway
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Liver
FC
CE
CE
CE
CE
CE
CE
LDL
HDL
TGTG
LDL receptor
LPLFC
TG
Adipose andother tissues
TG
LiverLDL receptor
Adiposetissue
FFA
FFA
Newsynthesis
Cell inperipheral tissue
VLDL
LCAT ABCA1
Endogenous pathway
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Liver
FC
CE
CE
CE
CE
CE
CE
LDL
HDL
TGTG
LDL receptor
LPLFC
TG
Adipose andother tissues
TG
LiverLDL receptor
Adiposetissue
FC
FFA
FFA
Newsynthesis
Cell inperipheral tissue
VLDL
Bile
LCAT ABCA1
Endogenous pathway
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Liver
FC
CE
CE
CE
CE
CE
Cell inperipheral tissue
CE
LDL
HDL
TGTG
LDL receptor
LPLFC
TG
Adipose andother tissues
TG
LiverLDL receptor
Adiposetissue
Bile
FC
FFA
FFA
Newsynthesis
VLDL
CETP
LCAT ABCA1
Endogenous pathway
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Formation and metabolism of HDL
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Surface monolayer ofphospholipidsand free cholesterol
Hydrophobic core of triglycerideand cholesteryl esters
apoA-I
apoA-II
Structure of HDL
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HDL Charge and shape
Discoidal
Spherical
Lipid-poor apoA-I Prebeta mobility
Prebeta mobility
Alpha mobility
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HDL2aHDL2b HDL3cHDL3bHDL3a
PARTICLE SIZE
APOLIPOPROTEIN COMPOSITIONPARTICLE SHAPE
Discoidal
Spherical A-I HDL A-I/A-II HDL
Lipid-poor apoA-I
HDL Subpopulations
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LIVER
Lipid-poor apoA-I
INTESTINE
Chylomicrons
Lipolysis
Formation of HDL
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Lipid-poor apoA-I
Discoidal HDL
ABCA-1
phospholipid,cholesterol
Cellmembrane
Lipidation of apoA-I to form discoidal HDL
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CE
SphericalHDL
DiscoidalHDL
LCATfreecholesterol
cholesterylesters
Free cholesterol transferred from cell membranes (including liver and intestine)
LiverIntestine
apoA-I
Role of LCAT in formation of spherical HDL
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HDL
VLDL/LDL
CE
Liver
Bile
CE
SR-B1
LDL-R
CE
FC
FC
SR-B1
LCATExtrahepatic Tissues
(including the artery wall
Free Cholesterol
CETP
Role of CETP and SRB1 in HDL metabolism
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Plasma lipoproteins
•Why do we have plasma lipoproteins?
•What are plasma lipoproteins?
•What is the metabolism of plasma lipoproteins?
•What is the relationship of plasma
lipoproteins to atherosclerosis?
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ATHEROSCLEROSIS
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AdhesionMolecule
Monocyte
Intima
Vessel Lumen
EndotheliumMCP-1
Macrophage Foam Cell
ATHEROSCLEROSIS
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Lipoprotein classes and atherosclerosis
Chylomicrons,VLDL, and theircatabolic remnants
LDL HDL
Pro-atherogenic Anti-atherogenic
Non-HDL
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AdhesionMolecule
Monocyte
Intima
Vessel Lumen
Endothelium
LDL
LDLMCP-1
Cytokines
Foam Cell
MODIFIED LDL
ROLE OF LDLs IN CAUSING ATHEROSCLEROSIS
Macrophage
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It has been proven beyond all doubt in many large clinical trials that reducing level of LDL cholesterol reduces the risk of having a cardiovascular event
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010
2030
400
40 80
(mg/dL)
4SWOS
CARELIPID
AFCAPS
50
HPS
ASCOT
ALLHAT
CARDS
JUPITER
TNT
SEARCH
IDEAL
RE
DU
CTI
ON
IN M
CV
Es
EVEN
TS (
%)
LRC
Posch
REDUCTION IN LDL CHOLESTEROL
IMPROVE-IT
CLINICAL INTERVENTION TRIALS
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Lipoprotein classes and atherosclerosis
Chylomicrons,VLDL, and theircatabolic remnants
LDL HDL
Pro-atherogenic Anti-atherogenic
Non-HDL
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AdhesionMolecule
Monocyte
Intima
Vessel Lumen
Endothelium
TRL remnants
MCP-1
Cytokines
Foam Cell
Modified TRL remnants
ROLE OF TRIGLYCERIDE-RICH LIPOPROTEINS (TRLS) IN CAUSING ATHEROSCLEROSIS
Macrophage
TRL remnants
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It is likely (but still not proven) that reducing levels of triglyceride-rich lipoproteins will reduce the risk of having a cardiovascular event
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AdhesionMolecule
Monocyte
Intima
Vessel Lumen
Endothelium
LDL
LDLMCP-1
Cytokines
Foam Cell
HDL PROMOTE CHOLESTEROL EFFLUX
HDL INHIBIT ADHESION MOLECULE EXPRESSION
MODIFIED LDL
HDL INHIBITOXIDATION OF LDL
HDL INHIBIT MCP-1 EXPRESSION
INHIBITION OF ATHEROSCLEROSIS BY HDLs
Macrophage
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It is possible (but not proven) that increasing levels of HDLs will reduce the risk of having a cardiovascular event
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Conclusions• Plasma lipoproteins transport triglyceride and
cholesterol through plasma between tissues
• LDLs and the remnants of triglyceride-rich lipoproteins cause atherosclerosis, while HDLs protect
• Reducing plasma levels of LDL cholesterol reduces the risk of having a cardiovascular event
• It is still not known whether decreasing triglyceride-rich lipoproteins or increasing HDL levels reduce cardiovascular risk