GSE
"The Cholesterol Players" - the lipoproteins involved in atherosclerosis
"The Lipoprotein Players" in atherosclerosis -
LDL, HDL, Lipoprotein(a)
Lipoproteins TRANSPORT LIPIDS in water-based blood
Since waxy cholesterol and fat are insoluble in water, they
are transported in our "watery" blood and lymph inside spherical transporter
capsules, called Lipoproteins. A single
layer of phospholipids and "free" cholesterol encases the water-hating
lipid core of triglycerides and cholesterol esters. Lipoproteins can carry, pick
up or drop off cholesterol and fats.
Apolipoprotein - "SUPERVISE LIPOPROTEINS"
Encircle lipoproteins to Regulate metabolism/uptake of lipoproteins
An apolipoprotein
(a.k.a. apoprotein) i s a coiled protein chain that
drapes around a lipoprotein. Examples of apolipoproteins
are Apo-A1, Apo-B100, and Apo (a)
- Keeps lipoproteins water-soluble
for circulation in blood and lymph. Binds fat-soluble lipids
to form water-soluble lipoproteins ;
- Helps maintain
the structural integrity of the lipoprotein
- Can be
a receptor ligand. As the "key" to open a receptor "lock"
it can bind lipoproteins to cell surface receptors for interaction in tissues
• Apo-B100 and Apo-E bind
to LDL-receptors. E.g. when a cell requires cholesterol,
it synthesizes and inserts LDL receptors into its plasma membrane. LDL particles
(lipoproteins) in the blood stream can then bind (via apolipoprotein) to these extracellular
LDL receptors.
• Apo-AI bind to HDL receptors;
Apo(a) has binding sites
(which act as "grappling hooks") that
can bind to lysine or proline residues exposed in damaged arterial walls .
Enables
Lipoprotein (a) to orchestrate plaque formation for damage repair;
- Identifies
the lipoprotein's type and determines from which cells cholesterol will be removed
and to where it will be supplied
- Act as
enzyme cofactors
- Examples
of apolipoproteins include:
• Apo-AI - major protein content of
HDL
• Apo-A4 - considered to be primarily
involved in intestinal lipid absorption
• Apo-B100 -
component of LDL and Lp(a) particles
• Apo-E - is a blood plasma protein;
binds to a specific receptor on liver and peripheral cells; mediates LDL transport
and uptake of cholesterol / lipids;
• Apo(a) -attached
to Apo-B100 as a component of Lipoprotein (a)
LDL (Low Density Lipoprotein)
(Draped with a single Apo B100 apoprotein)
LDL (Low Density Lipoprotein) - this
lipoprotein carries cholesterol TO
HDL (High Density Lipoprotein)
(Mainly draped with Apo A1)
HDL -
shuttles cholesterol AWAY FROM tissues, including your arteries HDL takes cholesterol
back to your liver to be recycled Note that the body considers
that cholesterol is "precious" enough to be conserved
Lipoprotein (a)
(The little "a" stands for adhesive)
Lp(a) is basically an LDL, with an attached "sticky"
apolipoprotein, called Apo(a) - Like LDL cholesterol,
Lp(a) contains an apolipoprotein called Apo B100, some phospholipids, and cholesterol
itself, but in Lp(a), the Apo B100 is chemically
(covalently) bonded to an additional large apolipoprotein known as Apo(a) ,
which makes Lp(a) behave differently than LDL.
The presence of Apo(a) prevents Apo B100 of LDL binding to
an LDL receptor
- Lp(a) carries
substantial amounts of cholesterol - which can be readily extracted and accumulated
at damage sites.
- Apo(a)
is expressed by liver cells (hepatocytes) and the
assembly of Apo(a) and LDL particles takes place in the liver
- Lp(a) is a
major independent risk factor for cardiovascular disease
- in an attempt to patch lesions in the endothelial blood vessel wall and in response
to an ascorbate deficiency, the liver manufactures
cholesterol and its transporters Lp(a) and LDL. Both of these are "sticky",
making them perfect for the job, although Lp(a) is much better in its patching ability.
Apo(a) - "Grappling Hook"
"Sticky"Apo(a) has lysine and proline binding
sites which it can use as "grappling hooks" to attach to lysine /proline
residues
Attach either on:
(1) Molecules exposed in the extra cellular matrix
(ECM) when arterial wall is damaged
-
Lp(a) Binds to damaged arterial wall to form atherosclerotic plaques -
Many U.S. National Medical Database reports confirm that "Sticky"Apo(a)
targets the Lp(a) particle to damaged sites, adhering to amino acid (particularly
lysine and proline) residues of collagen and elastin molecules, fibronectin, fibrinogen,
GAGs, and proteoglycans exposed in the extracellular matrix (ECM)* of a damaged
blood vessel wall (Adhesion is determined by the presence of calcium and magnesium
ions).
*Proteoglycans are themajor components of ECM
(the space between cells in an organism), they form large complexes to other proteoglycans,
to hyalauran and to fibrous matrix proteins, such as collagen and elastin.
Think of an LBS on an Lp(a) molecule as a simple lock
Or
(2) Fibrin (in a clot)
Lp(a) binds to fibrin
-
Apo(a) prevents blood clot breakdown - blood coagulation
is a complex event whereby platelets are trapped by fibrin (a thread-like protein)
to form a plug to prevent bleeding.
• In normal hemostasis, a blood clot is eventually
no longer required and is dissolved when lysine/proline residues on fibrin bind
to lysine/proline binding sites on plasminogen - the precursor to the
plasmin enzyme which dissolves the blood clot;
• However, being structurally similar to plasminogen,
Apo(a) also has an affinity for lysine residues on fibrin and so inhibits the
binding of plasminogen - preventin g the formation of plasmin for
breaking down blood clots.
Two concurrent pathways produce
THROMBIN, which coagulates blood. Thrombin converts
soluble fibrinogen to insoluble fibrin and activates platelets,
and red blood cells, enmeshed
in a network of fibrin molecules
over the wound site.
Thrombin production
is initiated by:
(1)
Tissue Factor (TF) expressed on the cell surface of the following
TF-expressing cells in response to trauma (called
extrinsic pathway):
•
Cells not normally exposed to flowing blood,
when exposed by vessel damage. Such as sub-endothelial
cells (e.g. smooth muscle cells ) and
cells surrounding blood vessels (e.g.
fibroblasts ) .
•
WBC Monocytes, endothelial cells and platelets.
TF expression is induced by inflammatory conditions
(i.e. influenced by pro-inflammatory cytokines, such as IL-1α,
IL-1β, and TNF-α) in response to trauma. Monocytes
also express TF when induced by type I
collagen, but expression is decreased by antioxidant
Poitevin S et al, Type I collagen induces
tissue factor expression and MMP-9 production in human primary monocytes
through a redox-sensitive pathway, 2008;
(2)
Blood contact with exposed molecules in damaged sub-endothelial
surface (called intrinsic pathway).
Blood contact activation pathway produces thrombin without requiring
TF. Amplifies first pathway.
In Atherosclerosis - Size Does Matter :)
The size of the cholesterol-carrying lipoprotein
particle determines if it can fit through the gap between the endothelial cells
lining the artery - which is about 26nm(1
nanometer = 10 -9 meter).
- LDL
particles are in the range from 20-30 nm, those < 25.8 nM can get through
easily - those > 26.3 nm can not. The presence of
small LDL particles is associated with the degree of atherosclerosis.
- HDL
particles ranging from 5-10 nm easily pass through the endothelial cell gaps
