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Plasma Lipoproteins

ILOs

Classify the different metabolic pathways of


lipids, lipoproteins and ketones bodies and
factors affecting their blood level.
Categorize the related metabolic disorders
and their clinical application on biochemical
and molecular basis.
Plasma Lipoproteins
What are plasma lipoproteins?
Spherical macromolecular complexes of:
Lipids + specific proteins (apo-proteins)
They includes:
1. Chylomicron
2. Very low density lipoproteins (VLDL)
3. Low density lipoproteins (LDL)
4. High density lipoproteins (HDL)
How can lipoproteins Differ?
They differ according to:
1. Composition of lipids to proteins
2. Size
3. Density
Functions of Lipoproteins

Transport lipids in plasma by the protein

portion (keep lipids soluble)

Transporting their lipid content to & from

tissues
Composition of Plasma Lipoproteins
Neutral core (TAG, exogenous or de novo,
cholesterol esters)
Amphipathic apolipoprotein
Phospholipids
Cholesterol
Size & Density
Chylomicrons: largest in size, lowest
in density, highest in lipids & lowest
in proteins
VLDL & LDL: denser, higher ratio of protein to lipid than
chylomicrons
HDL: densest
N.B. lipoprotein particles constantly interchange lipids &
proteins with each other making them variable
N.B. lipoproteins can be separated by electrophoresis
(mobility) or by ultracentrifugation (density)
Apolipoproteins
The apolipoproteins associated with lipoprotein
particles have a number of diverse functions
Proteins in nature
Function:
1.has recognition site for cell-surface receptors
2.serve as activators or coenzyme for lipoprotein
metabolism
3.important for lipoprotein function
4.Some are freely transferred between lipoproteins
Classes of apolipoproteins
A, B, C, D, E are major classes
Subclasses: apo A-1, apo C-II
N.B. function of all apolipoproteins are not
yet known
Metabolism of Chylomicrons CM
Site: intestinal mucosal cells
Function: carry dietary TAG, chol., fat-soluble vit., chol.
esters & lipids made in intestinal cells to peripheral
tissues.
Synthesis of apolipoproteins :
Apo B-48 is unique to CM
Synthesized in rough endoplasmic reticulum (RER)
Named 48 because 48% of n-terminal protein is coded
by apo B gene
Composition of CM Apoprotein
Apo B-48
Apo C-II from HDL
Apo E from HDL
Assembly of CM:
Requires microsomal TAG transfer protein to load apo
B-48 with lipids (TAG, Chol. phospholipids)
Synthesis occurs in ER golgi packed in secretory
vesicles fused with plasma membrane releasing
lipoproteins lymphatic system blood
Modification of Nascent CM
Intestinal mucosal cells produce nascent CM
Called nascent because it is functionally
incomplete
Once reaches plasma, CM particles receive apo E
& apo C-II from HDL
Apo C-II is activator of lipoprotein lipase that
degrades TAG in CM
Formation of CM Remnant
As CM circulates & its TAG degrades by
lipoprotein lipase, apo C is returned to HDL
remnant CM liver where its cell
membrane can recognize apo E (receptor)
to take up CM remnant by endocytosis
degradation releasing AA, cholesterol & FA
Lipoprotein lipase
Lipoprotein lipase is extra-cellular enzyme of
capillary walls of adipose tissue, cardiac &
skeletal muscle, not found in liver
Activated by apo C-II
Hydrolyzes TAG in CM FA + glycerol
FA either stored by adipose tissues or generate
energy by muscle
Glycerol liver for lipid synthesis, glycolysis or
gluconeogenesis
Metabolism of VLDL
Site of production: Liver
Composition: predominately TAG, apo B-100&
obtain apo C-II & apo E from circulating HDL
Function: carry TAG from liver to peripheral
tissues
apo C-II is required for activation of lipoprotein
lipase
Modification of circulating VLDL
TAG is degraded from VLDL by lipoprotein
lipase particles decrease in size & gets
denser
Apo C & E return to HDL
TAG goes to HDL & Cholesterol ester (CE)
from HDL goes to VLDL (exchange
mechanism by CE transfer protein) fig18.18
Production of LDL from VLDL
VLDL in plasma LDL + IDL (VLDL
remnant)
IDL can be taken up by cells via receptor-
mediated endocytosis using apo E (apo E
isoforms: E2, E3, E4)
Apo E2 binds poorly to receptors
Metabolism of VLDL
In peripheral tissues, VLDL-TAG are digested by
LPL, and VLDL is converted to IDL.
IDL returns to the liver, is taken up by
endocytosis, and is degraded by lysosomal
enzymes. IDL can also further degradation,
forming LDL.
LDL reacts with receptors on various cells and is
digested by lysosomal enzymes.
Metabolism of LDL
Composition: 50% cholesterol & CE, apo 100
Function: provide cholesterol from the liver to
peripheral tissues
Mechanism of LDL uptake: by cell-surface membrane
LDL receptors that recognize apo B-100 (LDL) or apo E
(VLDL)
These receptor are called apo B-100/apo E receptors
Metabolism of HDL (good Cholesterol carrier)

Heterogeneous, secreted into blood from liver &


intestine
Structure: nascent HDL contains PL, apo A,C & E fig.18.23
N.B PL solubilize cholesterol
Function: 1. reservoir of apolipoproteins apo C-II VLDL
& chylomicrons, apo E is required for receptor-mediated
endocytosis of IDLs & chylomicron remnants
2. activator of lipoprotein lipase
3. Uptake of cholesterol from other lipoproteins & cell
membrane
4.Esterification of Chol. in HDL by plasma
phosphatidylcholine : chol.acyltransferase (PCAT)
[also known as LCAT L for lecithin]
LCAT binds to nascent HDL & is activated by apo
A-1
5.Selective transfer of chol. from peripheral cells
to HDL & from HDL to liver for bile acid &
hormone synthesis mediated by scavenger
receptor class B-1 (SR-B1)
key for chol. Homeostasis, plasma HDL
atherosclerosis
Metabolism of HDL (good Cholesterol carrier)
HDL is a reservoir of apolipoproteins:
HDL particles serve as a circulating reservoir of
apo C ll (the apolipoprotein that is transferred to
VLDL and chylomicrons, and is an activator of
lipoprotein lipase),
and apo E (the apolipoprotein required for the
receptor-mediated endocytosis of IDLs and
chylomicron remnants
Apo C ll and Apo E are transferred back to HDL
following digestion of TAG of chylomicrons and
VLDL.
HDL uptake of unesterified cholesterol:

Nascent HDL are disk-shaped particles containing


primarily phospholipid (largely phosphatidylcholine) and
apolipoproteins A, C, and E. They are rapidly converted to
spherical particles as they accumulate cholesterol.

[Note: HDL particles are excellent acceptors of


unesterified cholesterol (both from other lipoproteins
particles and from cell membranes) as a result of their
high concentration of phospholipids, which are important
solubilizers of cholesterol.]
Esterification of cholesterol:
When cholesterol is taken up by HDL, it is immediately
esterified by the plasma enzyme
phosphatidylcholine:cholesterol acyltransferase (PCAT,
also known as LCAT)
This enzyme is synthesized by the liver.
PCAT binds to nascent HDLs, and is activated by apo A-1
PCAT transfers the fatty acid from carbon 2 of
phosphatidylcholine to cholesterol. This produces a
hydrphobic cholesteryl ester. As cholesterol esters
accumulate in the core of lipoprotein
HDL transfers cholesterol esters to other
lipoproteins in exchange for various lipids.
Cholesterol ester transfer protein (CETP)
mediates this exchange
HDL and other lipoproteins carry the
cholesterol esters back to the liver.
References

Mary K. Campbell and Shawn O. Farrell; Biochemistry; 6th edition 2007; Brooks

Cole, ISBN 0495390410.

Walsh, G; Biopharmaceutical: Biochemistry & Biotechnology; Wiley; ISBN

0470843276.

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