This document discusses lipoprotein metabolism and structure. It describes the different lipoproteins including chylomicrons, VLDL, IDL, LDL, and HDL. It outlines the roles of apoproteins and how lipoproteins transport triglycerides and cholesterol through the body. The pathways of exogenous and endogenous cholesterol are summarized along with lipoprotein processing and targets for treating dyslipidemia.
2. Outline
• Introduction – Structure and Function
• Apoproteins
• Chylomicron Metabolism
• VLDL, IDL & LDL Metabolism
• HDL & Reverse cholesterol transport
• Targets for Treating Dyslipidemia
3. Structure of lipoprotein
INTEGRAL APOPROTEINS
MONOLAYER OF PHOSPHOLIPID
AND CHOLESTERLOL
CHOLESTEROL
CORE
ESTERS
TRIGLYCERIDES
PERIPHERAL APOPROTEINS
5. 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, •Absorb cholesterol form peripheral tissues
apoD and transport it to liver
•Reservoir for exchange of lipoproteins in
VLDL and Chylomicron metabolism
6. Apoproteins:
o Regulate the metabolism
of lipoproteins by
modulating the activity of
enzymes
o Mediate the receptor
mediated uptake of
lipoproteins
Two kinds
1. Integral proteins : Name Lipoprotein Function
• apoA-I
Apo-A Name Lipoprotein
Name Lipoprotein Function Function Activates LCAT
HDL, Nascent
chylomicrons Structural
• Apo-B (B-48 &B-100)VLDL, IDL
apoC-I
apoB-100 HDL, IDL, LDL
VLDL, Activator of LCAT
Structural
Name apoA-II
Chylomicrons
Lipoprotein SynthesisFunction Structural
HDL, Nascent
and secretion of VLDL
2. PeripheralapoC-II Chylomicrons Binds to LDL ReceptorLipoprotein
proteins: VLDL, IDL chylomicrons to receptor on the
apoE HDL, Activator of
Binds
• Apo- C ApoB-48 HDL, VLDL, IDL Structural membrane of liver
Chylomicrons
Chylomicrons, lipase (LPL)
cell
• Apo- E (RNA Chylomicron
apoC-III Chylomicrons
apoD HDL, SynthesisStabilizes surface exchange
and secretion of
Cholestreyl ester
EDITING) HDL, VLDL, IDL Chylomicrons
remnant
Chylomicrons nascent
14. Hepatic uptake of Remnant Particles
CM OR VLDL
REMNANT
HSPG
Sequestration
HEPATIC LIPASE Space of Disse
Lipolysis
Uptake
HEPATOCYTE
LDL-R LRP LRP-HSPG HSPG
18. VLDL/ CM Remnant Albumin
Phospholipids
Cholesterol
PLTP
LCAT
CELL
CETP
HDL
19. Statins: Fibric Acids
HMG CoA Reductase •Reduces
Bile Acid inhibitors synthesis of VLDL
Seqestrants in liver
•Bind and remove •Increases
bile in intestine catabolism of
•Increases VLDL
cholesterol
conversion to bile
Cholesterol
Absorption Inhibitor
Ezetimibe:
•Inhibits transporter
protein on surface of
intestinal absorptive
cells.
•Blocks uptake of
dietary cholesterol
in small intestine.
26. ABCA1 Transporter/Receptor
Large 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.
27. 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.
28. Modification of LDL
LDL
Apo B-100
Derivatization: Oxidation:
Aldehydes Degradation of
Glucosylation B-100 by reactive
eg. diabetes oxygen species
Derivatized Oxidized
LDL LDL
29. LDL and Atherosclerosis
Fitting the pieces together
Elevated LDL: Increased residence time in plasma
Increased modification/oxidation of LDL
Monocyte
Endothelial
cells
oxLDL
Artery oxLDL (stimulates cytokine secretion)
wall
Macrophage
Smooth muscle cell
proliferation
Macrophage foam cell
