Transcript Plasma Lipoproteins

Plasma Lipoproteins
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What are plasma lipoproteins?
Spherical macromolecular complexes of:
Lipids + specific proteins (apo-proteins)
They includes:
Chylomicron
Very low density lipoproteins (VLDL)
Low density lipoproteins (LDL)
High density lipoproteins (HDL)
How can lipoproteins Differ?
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They differ according to:
Composition of lipids to proteins
Size
Density
Functions of Lipoproteins
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Transport lipids in plasma by the protein
portion (keep lipids soluble)
Transporting their lipid content to &
from tissues
N.B. In humans, the transport system is less
perfect than in other animals cholesterol
deposition in tissues atherosclerosis
Composition of Plasma Lipoproteins
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Neutral core (TAG, exogenous or de novo,
cholesterol esters)
Amphipathic apolipoprotein
Phospholipids
Cholesterol
Size & Density
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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
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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
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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
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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
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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
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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
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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
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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
Type 1 hyperlipoproteinemia or familial
lipoprotein Lipase deficiency
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Patients deficient in lipoprotein lipase or
apo C-II
Accumulation of CM in plasma
N.B. lipoprotein lipase is stimulated by
insulin
Metabolism of VLDL
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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
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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
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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
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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 with receptors on
various cells and is digested by lysosomal
enzymes.
A beta lipoproteinemia
Hypolipoproteinemia
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Defect in TAG transfer protein
Inability to load apo B with lipid
No chylomicrons or VLDLs
TAG accumulates in liver & intestine
Familial Type III hyperlipoproteinemia
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Also called familial
dysbetalipoproteinemia
Patients are deficient in apo E2
 Clearance of CM remnant & IDL
Hypercholesterolemia
Metabolism of LDL
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Composition: 50% cholesterol & CE, apo 100
Function: provide cholesterol to peripheral tissues
or return it to liver
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
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The primary function of LDL particles is to
provide cholesterol to the peripheral tissues
(or return it to the liver).
LDL receptors are negatively charged
glycoproteins that are clustered in pits on
cell membranes. The intracellular side of the
pit is coated with the protein clathrin, which
stabilizes the shape of the pit
After binding, the LDL-receptor complex is
internalized by endocytosis
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The pH of the endosome falls (due to
the proton-pumping activity of
endosomal ATPase), which allows
separation of the LDL from its receptor.
The receptors then migrate to one side
of the endosome, whereas the LDLs
stay free within the lumen of the
vesicle. [Note: This structure is called
CURL Compartment for Uncoupling for
Receptor and Ligand]
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The receptors can be recycled, whereas the
lipoprotein remnants in the vesicle are
transferred to lysosomes and degraded by
lysosomal (hydrolytic) enzymes, releasing
free cholesterol, amino acids, fatty acids, and
phospholipids.
These compounds can be reutilized by the
cell.
LDL Receptors
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-ve charged cell membrane glycoprotein
Intracellular side is coated with protein
clathrin to stabilize the receptor
LDL receptor deficiency   plasma LDL &
cholesterol  type II hyperlipidemia (familial
hypercholest.)
T3 cause +ve effect on LDL binding to its
receptors
Hypothyroidism  hypercholesterolemia
LDL Receptors (continue)
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Vesicle containing LDL loses its clathrin &
fuses with other vesicles  large vesicles 
endosomes
 pH of endosomes due to proton pump
ATPase  CURL LDL + free receptor
N.B.CURL is Compartment for Uncoupling of
Receptor & Ligand
Receptor can be recycled (fig 18.20)
Effect of endocytosed cholesterol on
cellular cholesterol homeostasis
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The chylomicron remnant-, IDL-, and LDLderived cholesterol affects cellular cholesterol
content in several ways.
First, HMG CoA reductase is inhibited by high
cholesterol, as a result of which, de novo
cholesterol synthesis decreases.
Second, synthesis of new LDL receptor
protein is reduced by decreasing the
expression of the LDL receptor gene, thus
limiting further entry of LDL cholesterol into
cells
Effect of endocytosed cholesterol on
cellular cholesterol homeostasis
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Third, if the cholesterol is not required
immediately for some structural or synthetic
purpose, it is esterified by acyl CoA
cholesterol acyltransferase (ACAT) transfers
a fatty acid from a fatty acyl CoA derivative to
cholesterol, producing a cholesteryl ester that
can be stored in the cell.
The activity of ACAT is enhanced in the
presence of increased intracellular
cholesterol.
Macrophage Scavenger
receptors
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In addition to the highly specific and
regulated receptor-mediated pathway for LDL
uptake, macrophages possess high levels of
scavenger receptor activity.
These receptors, known as scavenger
receptor class A (SR-A), can bind a broad
range of ligands, and mediate the
endocytosis of chemically modified LDL.
Macrophage Scavenger
receptors
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Chemical modifications that convert circulating LDL
into ligands that can be recognized by SR-A receptors
include oxidation of the lipid components and
apolipoprotein B.
Unlike the LDL receptor, the scavenger receptor is not
down-regulated in response to increased intracellular
cholesterol.
Cholesteryl esters accumulate in macrophages and
cause their transformation into "foam" cells, which
participate in the formation of atherosclerotic
plaque
Macrophage Scavenger receptors
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Receptor: scavenger receptor class A (SR-A)
Ligand: oxidized LDL (lipid + apo B)
SR-A is not down-regulated to increased
intracellular cholesterol  cholesterol in
macrophages  foam cells  atherosclerosis
plaque (fig 18.22)
Lipoprotein (a) in heart disease:
Is identical to LDL & linked to apo B-100
It increases the risk for coronary heart disease
Metabolism of HDL (good Cholesterol carrier)
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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
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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)
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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.
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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.]
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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)
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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
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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.
Activity
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Schematic diagram of lipogenesis and
lipolysis
Schematic diagram of ketogenesis and
ketolysis
Schematic diagram cholesterol synthesis
Discuss types and functions of plasma
lipoproteins.