Lipoproteins

Lipoproteins
particles found in plasma that transport lipids including
cholesterol
Lipoproteins are ordinates mixtures of lipids with proteins
lipoprotein classes
chylomicrons: take lipids from small intestine through lymph cells
very low density lipoproteins (VLDL)
intermediate density lipoproteins (IDL)
low density lipoproteins (LDL)
high density lipoproteins (HDL)

Lipoprotein structure

LDL
molecule

The Players Lipids

Triacylglycerol

Phospholipids

Cholesterol
Cholesteryl esters

The apolipoproteins

major components of lipoproteins

often referred to as aproteins
classified by alphabetical designation (A thru E)
the use of roman numeral suffix describes the order
in which the apolipoprotein emerge from a
chromatographic column
responsible for recognition of particle by receptors

Apolipoprotein Structure:
Amphipathic -helices (polar along one surface of a
helix and hydrophobic along the other side) are
common structural motifs.
One view is that these -helices may float on the
phospholipid surface of the lipoprotein.
Some domains of apolipoproteins have roles in
interaction of lipoproteins with cell surface
receptors.

Apolipoprotein A-I (apoA-I) of human

HDL, in the absence of lipid, is found
consist of an N-terminal antiparallel 4-helix
bundle & a C-terminal domain that is also
-helical.

Chylomicrons,
VLDL, and
their catabolic
remnants

LDL

> 30 nm

2022 nm

HDL

915 nm

D<1.006 g/ml D=1.019-1.063g/mlD=1.063-1.21 g/ml

There is special interest in the structure and

stability of apolipoprotein E.
In addition to being a constituent of various
lipoproteins, e.g. VLDL & HDL, a variant of
apolipoprotein E, designated apoE4, is
implicated in Alzheimer's disease and other
neurological conditions.
Having the apoE4 isoform is a major risk
factor for Alzheimer's disease.
Fragments of apoE4 are found to generate
intracellular deposits resembling the
neurofibrillary tangles seen in Alzheimer's
disease.

Chylomicron
formed through extrusion of resynthesized
triglycerides from the mucosal cells into the
intestinal lacteals
flow through the thoracic ducts into the
suclavian veins
degraded to remnants by the action of
lipoprotein lipase (LpL) which is located on
capillary endothelial cell surface
remnants are taken up by liver parenchymal
cells due to apoE-III and apoE-IV isoform
recognition sites

Chylomicron
Metabolism
Long-chain fatty
acids are reesterified into
triacylglycerols in
the gut and
transferred;
chylomicrons
which contain
apoB48 are
synthesized and
secreted into the
blood via the
lymphatic
circulation

Chylomicron
Metabolism
ApoCs, apoE and
cholesteryl esters are
acquired from HDL in
circulation.
ApoA-I and apoA-IV
may be acquired from
either the intestine or
from HDL in
circulation.

Chylomicron
Metabolism
ApoC-II activates
lipoprotein lipase which
catalyses the hydrolysis
of triacylglycerols

Chylomicron
Metabolism
Apolipoproteins are
transferred back to HDL

Chylomicron
Metabolism
The chylomicron
remnant is taken up by
the apoB48/remnant
receptor in the liver

TG Rich: VLDL
Surface Monolayer
Phospholipids (12%)
Free Cholesterol (14%)
Protein (4%)

Hydrophobic Core
Triglyceride (65%)
Cholesteryl Esters (8%)

VLDL Biogenesis

Microsomal
TG transfer
protein
(MTP)

Facilitates the
translocation,
folding of apoB
and addition of
lipids to lipid
binding domains

TG and
cholesterol are
synthesized in
the liver as
VLDL which
contains apoB100

VLDL
Metabolism
Apo Cs and apoE and
cholesteryl ester are
acquired from HDL in
circulation

ApoC-II activates
lipoprotein lipase which
catalyses the hydrolysis
of TG

Fatty Acid Transport

VLDL
Metabolism
Apolipoproteins are
transferred back to HDL

The end product is a

VLDL remnant (IDL)

VLDL
Remnant
Uptake
The remnant particle (IDL),
if it contains apoE, can be
taken up by the
apoE/remanant receptor

VLDL
Conversion to
LDL
Further action on IDL by
hepatic lipase loses
additional apolipoproteins
(apoE) becomes and is
converted to LDL

CE Rich: LDL
Surface Monolayer
Phospholipids (25%)
Free Cholesterol (15%)
Protein (22%)

Hydrophobic Core
Triglyceride (5%)
Cholesteryl Esters
(35%)

Cholesterol and
Atherosclerosis,

LDL is removed by
apoB100 receptors
which are mainly
expressed in the
liver

LDL Metabolism

Hepatic
Lipase
Cholesteryl
ester transfer
protein

LDL Uptake by Tissues

Defects in the LDL receptor leads to familial hypercholesterolemia

Corneal arcus

Tendon xanthoma

Tendon xanthoma

CE Rich: HDL
Surface Monolayer
Phospholipids (25%)
Free Cholesterol (7%)
Protein (45%)

Hydrophobic Core
Triglyceride (5%)
Cholesteryl Esters
(18%)

Cholesterol and
Atherosclerosis,

HDL Subpopulations
Particle Shape

Apolipoprotein Composition

Discoidal

Spherical

A-I HDL

Particle Size

A-I/A-II HDL A-II HDL

Lipid Composition
TG, CE, and PL

HDL2b HDL2a HDL3a HDL3b HDL3c

HDL
Maturation
HDL is secreted in a
discoidal form from the liver
and gut.
As it acquires cholesterol
from tissues in the
circulation, it matures into a
spherical form through the
action of lecithin:cholesterol
acyl transferase

Cholesterol and
Atherosclerosis,

Nascent HDL (lipid-poor apoA-I) is produced by the liver and intestine

HDL Metabolism

Free cholesterol is acquired from peripheral tissues

HDL Metabolism

LCAT converts free cholesterol to cholesteryl

HDL Metabolism

A variety of enzymes interconvert HDL subspecies

HDL Metabolism

HDL Interconversions

Cholesterol
Homeostasis

Hepatic
Cholesterol
Metabolism

Hepatic
Cholesterol
Metabolism

Hepatic Cholesterol Synthesis

Only
pathway for
cholesterol
degradation

Rate Limiting

Energetically expensive; prefer

to conserve what is already
made/acquired LDL receptor
pathway

LDL Cellular Metabolism

LDL are taken up by the LDL Receptor into clathrin-coated pits

LDL dissociates from the receptor; the receptor recycles to the membrane

In the lysosome, lipids are deseterified; proteins are hydrolyzed

Increase in free cholesterol regulates decrease cholesterol synthesis

and uptake; increase cholesterol esterification

Hepatic
Cholesterol
Metabolism

When cholesterol accumulates

in cells, cholesterol is oxidized
to create oxysterols

Role of LXR and FXR

Development of
Athersoclerosis

Evolution and Progression of

Coronary Atherosclerosis

O cclusive
Thrombus

I ntimal I nu
j ry
Fatty Streak

Lipid- Rich
Plaque

Plaque
Disruption

Atherogenic Ris k Fac tors

0

20

Fibr omuscular

Thrombus

Lysis

Response

O cclusion

Thrombogenic Ris k F ac tors

40

50

Age (years )

60

Endothelial Dysfunction

Ross, NEJM; 1999

Formation of Fatty Streak

Formation of Advanced,
Complicated Lesion

Development of Unstable
Fibrous Plaque
Rupture or ulceration of
fibrous cap rapidly leads to
thrombosis.
Occurs primarily at sites of
thinning of the fibrous cap.
Thinning is a result of
continuing influx of and
activation of macrophages
which release
metalloproteinases and other
proteolytic enzymes.
These enzymes degrade the
matrix which can lead to
hemorrhage and thrombus
formation

Thrombus

Fibrous cap

Plaque Rupture with Thrombus

1 mm
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.

Lipid core