Lipoprotein metabolism, Shariq
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Transcript of Lipoprotein metabolism, Shariq
Lipoprotein metabolismSyed Shariq Naeem
Outline
• Introduction – Structure and Function• Apoproteins• Chylomicron Metabolism• VLDL, IDL & LDL Metabolism• HDL & Reverse cholesterol transport• Targets for Treating Dyslipidemia
CORECHOLESTEROL
ESTERS
TRIGLYCERIDES
MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOL
INTEGRAL APOPROTEINS
PERIPHERAL APOPROTEINS
Structure of lipoprotein
Nomenclature of lipoproteinsDiameter
nmProtein
%Triglycerides
%Cholesteryl esters %
Chylomicron 75-1200 1 88 3
VLDL 30-80 10 56 15
IDL 25-30 10 29 34
LDL 18-25 ~20 13 48
HDL 5-12 ~50 13 30
Albumin Fatty acid complex
Lipoproteins Lipoprotein Apoproteins Function
Chylomicron apoB-48, apoC, apoE Transport TGs form intestine to liver/ other tissues
VLDL apoB-100, apoC, apoE Transport TGs from liver to adipose/ muscles.
IDL apoB-48, apoC, apoE Intermediary between VLDL and LDL
LDL apoB-48 Transport cholesterol to peripheral tissues.
HDL apoA, apoC, apoE, apoD
•Absorb cholesterol form peripheral tissues and transport it to liver•Reservoir for exchange of lipoproteins in VLDL and Chylomicron metabolism
Apoproteins:o Regulate the metabolism
of lipoproteins by modulating the activity of enzymes
oMediate the receptor mediated uptake of lipoproteins
Two kinds1. Integral proteins :
• Apo-A• Apo-B (B-48 &B-100)
2. Peripheral proteins:• Apo- C• Apo- E
Name Lipoprotein Function
apoA-I HDL, Nascent chylomicrons
Activates LCATStructural
apoA-II HDL, Nascent chylomicrons
Structural
Name Lipoprotein Function
apoB-100 VLDL, IDL, LDL StructuralSynthesis and secretion of VLDLBinds to LDL Receptor
ApoB-48(RNA EDITING)
Chylomicrons, Chylomicron remnant
StructuralSynthesis and secretion ofChylomicrons
Name Lipoprotein Function
apoC-I HDL, VLDL, IDL Chylomicrons
Activator of LCAT
apoC-II ChylomicronsHDL, VLDL, IDL
Activator of Lipoprotein lipase (LPL)
apoC-III ChylomicronsHDL, VLDL, IDL
Stabilizes surface
Name Lipoprotein Function
apoE HDL, VLDL, IDLChylomicrons
Binds to receptor on the cell membrane of liver
apoD HDL, Chylomicrons nascent
Cholestreyl ester exchange
Cholesterol biosynthesis
Exogenous PathwayChylomicron Processing
Duodenum
Fat
CCK
Bile salts
Micelles
Enterocytes
ACAT
Lacteal Thoracic duct Systemic circulation
apo B-48
apo-Capo-E
Chylomicron
Liver
Chylomicron
apo-B-48
apo-E
apo-C
Adipocyte
Chylomicron remnant
When TGs < 20% remaining, they loose apoC
apoE
VLDL
LDL-R Chylomicron remnant receptor
Endogenous PathwayVLDL Synthesis and Processing
Conversion of VLDL to LDLLDL Uptake
Liver
apo-B-100
TGs <50%
TGs <30%
VLDL Remnant
IDL
TGs < 10% Loses apoE & apoC
LDL
LDL-R
apo-B-100
Cell wall Aldosterone
CortisolSex hormones
apoB-100
VLDL
HDL
VLDL
LPL
Adipocyte &Myocyte
Remains attached to LPL
Hepatic uptake of Remnant Particles
CM OR VLDLREMNANT
HSPG
HEPATIC LIPASE
Sequestration
Lipolysis
Uptake
LDL-R LRP LRP-HSPG HSPG
Space of Disse
HEPATOCYTE
Reverse Cholesterol Transport – Role of HDLLCATCETP
• All cells can make Cholesterol
• Only HDL can pick up cholesterol from Peripheral Tissues
• Only the liver can degrade cholesterol
Liver
Pre-β-HDLABCA1
LCAT
apoA α -HDL
Hepatic lipase
SR-B1
apoA
VLDLREMNANT
VLDL/ CM Remnant
CELL
Phospholipids
Cholesterol
LCAT
Albumin
PLTP
CETP
HDL
Statins:HMG CoA ReductaseinhibitorsBile Acid
Seqestrants•Bind and remove bile in intestine•Increases cholesterol conversion to bile
Fibric Acids•Reduces synthesis of VLDL in liver•Increases catabolism of VLDL
Cholesterol Absorption Inhibitor Ezetimibe: •Inhibits transporter protein on surface of intestinal absorptive cells.•Blocks uptake of dietary cholesterol in small intestine.
Thank you
ABCA1 Transporter/ReceptorLarge plasma membrane spanning ATP dependent protein.
Essential for moving excess intracellular cholesterol and phospholipid to the plasma membrane.
Acts as a flipase, flipping cholesterol and phospholipid from inner leaflet of plasma membrane to outer leaflet.
Necessary for removing excess cholesterol from foam cells and preventing early steps in atherosclerosis.
ApoA-I is required for capturing the cholesterol released from the foam cell.
The Scavenger Receptor
(SR-A1 receptor)
How macrophages deal with oxidized or modified LDL
The scavenger receptor recognizes modified and/or oxidized LDL and internalizes the modified LDL.
Accumulation of these modified LDL in the cell leads to the accumulation of cholesterol droplets in the macrophage and the formation of foam cells.
Modification of LDL
LDL
Apo B-100
Derivatization:AldehydesGlucosylationeg. diabetes
Oxidation:Degradation of B-100 by reactiveoxygen species
Derivatized LDL
Oxidized LDL
LDL and AtherosclerosisFitting the pieces together
Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL
Artery wall
Monocyte
Endothelialcells
oxLDL
oxLDL (stimulates cytokine secretion)
Macrophage
Macrophage foam cell
Cytokines
Cytokines
Smooth muscle cellproliferation
HDL Protective RoleFitting the pieces together
oxLDL = oxidized LDLUC = unesterified cholesterol
ABCA1apoA-I
Endothelialcells
HDL
HDL
UC
PL
UC
Nascent HDL
HDL + UC
Macrophage foam cell
oxLDL
Monocyte
Arterywall
apo-B-48
apo-E
apo-C
apo-B-48
apo-E
apo-C
LCAT
Chylomicron remnant receptor
VLDL
LDL
LDL
SYNTHESIS OFCHOLESTEROL
SYNTHESIS OFLDL RECEPTORS
CHOLESTEROLESTERS
MEMBRANESSTEROIDSBILE ACIDS
HMG CoAReductase
ACAT
EXCESSCHOLESTEROL
LDLReceptors
DNA
RNA
INHIBITSINHIBITS
ACTIVATES
LDL DELIVERS CHOLESTEROL TO CELLS
Diameternm
Protein %
Triglycerides%
Cholesteryl esters %
Chylomicron 75-1200 1 88 3
VLDL 30-80 10 56 15
IDL 25-30 10 29 34
LDL 18-25 ~20 13 48
HDL 5-12 ~50 13 30
LDL-Receptors
Endosome Lysosome
Aminoacids
CholesterolLDL
Cholesteryl ester(storage)LDL
Receptors
HMG-CoAreductase
LDL
LDL Receptor (apoB-E receptor)
ACAT
Regulates cholesterol synthesis and plasma cholesterol levels