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.

1. Lipoprotein metabolism
Syed Shariq Naeem

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

4. Nomenclature of lipoproteins
Diameter Protein Triglycerides Cholestery
nm % % l 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

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

7. Cholesterol biosynthesis

9. Exogenous Pathway
Chylomicron Processing

10. apo B-48 Fat
CCK
Bile salts Duodenum
Chylomicron
Micelles
ACAT
Enterocytes
apo-C
apo-E
Lacteal Thoracic duct Systemic circulation

11. LDL-R Chylomicron remnant receptor
apo-B-48
VLDL
apo-E
apo-C Liver
Chylomicron apoE
Adipocyte
Chylomicron remnant
When TGs < 20% remaining, they loose apoC

12. Endogenous Pathway
VLDL Synthesis and Processing
Conversion of VLDL to LDL
LDL Uptake

13. apo-B-100
HDL
Liver
VLDL apo-B-100
TGs <50%
Remains
LPL
attached to
LPL Adipocyte & VLDL
VLDL Remnant Cell wall Myocyte
LDL-R
Aldosterone
TGs <30% Cortisol
Sex hormones
IDL
TGs < 10% Loses apoE & apoC
LDL apoB-100

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

15. Reverse Cholesterol Transport – Role
of HDL
LCAT
CETP

16. • All cells can make Cholesterol
• Only HDL can pick up cholesterol from
Peripheral Tissues
• Only the liver can degrade cholesterol

17. apoA
VLDL
REMNANT
Liver LCAT
Pre-β-HDL
SR-B1 ABCA1
apoA α -HDL
Hepatic
lipase

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.

20. Thank you

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

30. HDL Protective Role
Fitting the pieces together
HDL Monocyte
Endothelial
cells
oxLDL
HDL
Artery UC
wall
HDL + UC
apoA-I ABCA1
PL
UC oxLDL = oxidized LDL
Macrophage foam cell UC = unesterified cholesterol
Nascent HDL

31. apo-B-48
apo-E
apo-C
apo-B-48
apo-E
apo-C

32. VLDL
LCAT
Chylomicron remnant receptor

33. LDL DELIVERS CHOLESTEROL TO CELLS
LDL
LDL
Receptors
SYNTHESIS OF
CHOLESTEROL
SYNTHESIS OF
HMG CoA LDL RECEPTORS
Reductase
DNA
INHIBITS
INHIBITS
RNA
EXCESS
CHOLESTEROL
ACAT
ACTIVATES
MEMBRANES
STEROIDS CHOLESTEROL
BILE ACIDS ESTERS

35. Diameter Protein Triglycerides Cholestery
nm % % l 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

36. LDL Receptor (apoB-E receptor)
Regulates cholesterol synthesis and plasma cholesterol levels
HMG-CoA
reductase
Cholesteryl ester
LDL (storage)
Receptors
LDL-Receptors
ACA
T
Cholesterol
LDL LDL
Amino
Endosome Lysosome acids