Lipoproteins: Structure, classification, metabolism and significance

Dr. Ifat Ara Begum
Assistant Professor
Dept of Biochemistry
Dhaka Medical College

Spherical molecules of lipids and
proteins (apoproteins) =
amphipathic molecules

Lipids absorbed from the diet and
synthesized by the liver and adipose tissue
must be transported between various cells
and organs for utilization and storage.
Lipids are insoluble in water, the problem
of transportation in the aqueous plasma is
solved by associating nonpolar lipids
(triacylglycerols and cholesteryl esters) with
amphipathic lipids (phospholipids and
cholesterol) and proteins to make water-miscible
lipoproteins.

 Its objective is to solubilize lipids in
plasma to facilitate their transport in
biological system & provide efficient
mechanism for lipid delivery to the tissues
and lipid removal from the tissues.
 LPs possess the fundamental properties of
micelle except the fact that, micelle is
composed of amphipathic (polar) lipids
only.

 Lipoproteins consist of a nonpolar core and a
single surface layer of amphipathic lipids
 These are oriented so that their polar groups
face outward to the aqueous medium.
 The protein moiety of a lipoprotein is known as
an apolipoprotein or apoprotein.

 Some apolipoproteins are integral and
cannot be removed, whereas others can be
freely transferred to other lipoproteins.
So, constituents of LPs, in short, are:
TAG, cholesterol ester, PL, Free
cholesterol and apoprotein.

 Provide hydrophilic character to LP particle to
allow their transport in plasma
Maintains structural stability of LPs
 Determine the metabolic fate of LPs and allow
exchange of lipids between LPs
 Cofactor for enzymes of LP metabolism. e.g. Apo C
II for LPL, Apo A II for LCAT
 Inhibitors of enzyme. e.g. Apo C III & A II inhibit
LPL.
 Act as ligand to recognize LP receptors on cell
surface

 There are various types of lipoproteins:
 They differ in lipid and protein
composition
and therefore, they differ in:
- Size and density
- Electrophoretic mobility

 Lipoproteins with high lipid content will
have low density, larger size and so float
on centrifugation. Those with high
protein content sediment easily, have
compact size (decreasing size) and have a
high density
LDL- Highest Cholesterol
HDL – Highest protein, PL
CM – Highest TG

 93% of total body cholesterol resides in
intracellular compartment & only 7% is
found in plasma where cholesterol is carried
by : LDL (60-70%), HDL (20-30%) &
VLDL (10-15%)
 There are 3 other specialized LPs , all are
atherogenic: CMR (Chylomicron remnant),
VLDLR/IDL & Lp(a)

For triacylglycerols transport (TG-rich):
 Chylomicron: TG of dietary origin
 VLDL: TG of endogenous (hepatic)
synthesis
For cholesterol transport (cholesterol-rich):
LDL: Mainly free cholesterol
HDL: Mainly esterified cholesterol

Lp(a): An atherogenic lipoprotein
containing apo(a) and apo B.
 20-30% of people have levels
suggesting C-V risk.
 Black subjects have Lp(a)
normal range twice as high
as white and Asiatic subjects

 Apo(a) sequence similar to plasminogen,
and Lp(a)
interferes with spontaneous thrombolysis.
 Lp(a) levels highly genetic, resistant to
diet and drug
therapy, although niacin may help.

Lipoproteins:
Separation by –
Electrophoresis
Density
Size by
Electron Microscopy

LLIIPPOOPPRROOTTEEIINN LLIIPPAASSEE
LLPPLL
Apo C-II
+ +

LCAT( Lecithin Cholesterol Acyl
Transferase) enzyme catalyzes the
esterification of cholesterol to form
Cholesteryl ester.
The reaction can be represented as follows-
Lecithin + Cholesterol-> Lysolecithin+
Cholesteryl Ester

 Produced by liver and found attached with
hepatic sinusoidal endothelium
 Hydrolyzes TAG & PL of IDL, LDL & HDL
 Helps to convert IDL to LDL & large buoyant
LDL to small dense LDL
 Helps to complete the HDL cycle by
converting HDL2 to HDL3 to enhance the
RCT (Reverse cholesterol transport)

VLDL/ CHYLOMICRON
HDL
FC ,TAG
CE
Cholesterol Ester Transfer Protein

CCHHYYLLOOMMIICCRROONN
 Formed in the
intestinal
mucosal cells
 Rich in TG
 Contain
apo-B-48
 Apo-E
 Apo-C

 Assembled in intestinal mucosal cells
 Lowest density
 Largest size
 Highest % of lipids and lowest %
proteins
 Highest triacylglycerols (dietary origin)
 Carry dietary lipids to peripheral tissues
 Responsible for physiological milky
appearance of plasma (up to 2 hours
after meal)

 Synthesis of apo B-48 in enterocytes
 Synthesis & release of nascent Chylomicron
(CM): Absorbed end products of lipid
digestion on coming to enterocytes along
with newly synthesized lipids again form
cholesterol ester, PL & TAG. Now they
assemble with apo B-48 to make nascent
CM. Nascent CM is secreted into intestinal
lymphatics by exocytosis. CM moves via
thoracic duct into blood

 Modification of nascent CM in plasma:
CM receives apo C-II, apo E from HDL
on coming to blood
 Exchange of lipids with HDL: CM
receives CE from HDL & gives its TAG
and free cholesterol (FC) to HDL. This is
mediated by CETP (Cholesterol ester
transfer protein)

 Degradation of TAG of CM In peripheral
tissues by LPL & formation of CMR
(Chylomicron remnant):
LPL in capillary endothelial surface of
peripheral tissues (adipose/cardiac/skeletal
tissues) hydrolyzes TAG of CM to FA &
glycerol with the help of apo C-II
 FA moves to cells for storage/utilization
Glycerol goes to liver for further
metabolism
 Size of mature CM decreases by 75%. Now
apo C-II returns back to HDL & CM
becomes CMR (Cholesterol rich)

 Clearance of CMR by liver:
CMR goes to liver. Hepatocytes recognize
CMR with the help of apo E & then
internalize them by receptor mediated
endocytosis to metabolize the constituents of
CMR within hepatocyte. Just prior to
endocytosis, apo E is returned to HDL

VVLLDDLL
Synthesized in
the liver
Contain
apo-B-100,
C-II and
apo-E

There are striking similarities in the
mechanisms of formation of
Chylomicron by intestinal cells and of
VLDL by hepatic parenchymal cells

 Synthesis of apo B-100 in liver
 Assembly of VLDL, packaging &
release of nascent VLDL:
Hepatocytes synthesizes TAG, CE, PL
& free cholesterol (FC) endogenously
 Endogenously produced lipids assemble
with apo B-100 to make nascent VLDL
 Nascent VLDL is then secreted from the
liver by exocytosis to hepatic sinusoids &
thence to general circulation.

Modification of nascent VLDL in
plasma: On coming to blood VLDL,
receives apo C-II, apo E from HDL
Exchange of lipids with HDL: VLDL
receives with CE from HDL & in
exchange gives TAG & FC to HDL. This
is mediated by CETP (Cholesterol ester
transfer protein)

Degradation of TAG of VLDL in peripheral
tissues by LPL and formation of VLDLR:
LPL in capillary endothelial surface of
peripheral tissues ( mainly adipose tissues,
cardiac/skeletal muscles) hydrolyzes TAG of
VLDL to FA & glycerol, with the help of apo C-II.
 FA moves to cells for storage/ utilization
Glycerol is taken to liver for further metabolism
 Size of mature VLDL decreases by 75% now.
Apo C-II is returned back to HDL & VLDL
turns into VLDLR/IDL (Cholesterol rich)

Clearance of IDL:
 50% of IDL goes to liver. Hepatocyte
recognizes IDL with the help of apo E &
internalize them via receptor mediated
endocytosis for further metabolism. Just
prior to endocytosis, apo E is returned to
HDL
Remaining 50% of IDL in circulation
matures to LDL with return of apo E back
to HDL

LLDDLL
Contain
apoB-100
Contain
apoB-100

LDL carries about 70% of total plasma
cholesterol
High LDL-C level is well established
risk factor for development of coronary
heart disease
The diagnosis of a primary defect is
made after secondary defect causes have
been ruled out

 Produced in the circulation as the end
product of VLDL
 Compared to VLDL:
 It contains only apo B-100, Smaller size and
more dense
Less TG
 More cholesterol & cholesterol ester
 Transport cholesterol from liver to
peripheral tissues
 Uptake of LDL at tissue level by: LDL
receptor-mediated endocytosis , recognized
by apo B-100

 Formation of LDL in plasma from IDL:
 In plasma IDL, produced from VLDL,
returns apo E back to HDL. Now IDL
receives CE from HDL & in exchange gives
TAG and FC to HDL. This is mediated by
CETP.
Hepatic lipase hydrolyzes majority of the
remaining TAG & PL of IDL.
With these changes IDL matures to LDL ,
which is loaded with CE
LDL further receives CE from HDL in
exchange of TAG

 Metabolic fate of LDL:
70% is catabolized in liver
30% is catabolized in peripheral tissues
like muscle, steroidogenic organs, etc
Cellular uptake of LDL in liver &
peripheral tissues is mediated by
controlled receptor mediated endocytosis
via LDL receptor.

 Endocytosed LDL releases FC within the
cell which has 2 fates:
FC may be stored there as CE.
Esterification of FC to CE within cell is
catalyzed by ACAT (Acyl CoA
Cholesterol Acyl Transferase)
Released FC may be used for membrane
synthesis/ steroid synthesis/ bile acid
synthesis, depending on cellular need.

LDL: Receptor-Mediated Endocytosis

 Sometimes, LDL undergoes chemical
modification in circulation through chemical
assault by different types of endogenous
oxidants (like free radical) to produce
oxidized LDL (ox-LDL).
Ox-LDL is highly chemotactic & readily
endocytosed by macrophage via LDL
receptor independent pathway.
On excessive accumulation, macrophage
loaded with cholesterol turns into foam cells
that move to sub endothelial space . Here
they produce growth factors & cytokines to
initiate atherosclerotic plaque formation.

HHDDLL
Contain
Apo-A-I[
Major]
Apo-C
Apo-E
Contain
Apo-A-I[
Major]
Apo-C
Apo-E

Metabolism of HDL:
 Synthesis & secretion of nascent HDL to blood:
 It is produced mainly by liver & partly by
intestinal cells
Nascent HDL is a small discoidal PL bilayer
with FC, apo A, C & E
 Maturation of HDL in blood:
Nascent HDL binds with specific receptor
present on cell membrane of peripheral tissues
 FC efflux from peripheral cells to nascent
HDL down the concentration gradient

On coming to HDL, FC is immediately
converted to CE by LCAT (lecithin
cholesterol acyl transferase) & thereby
FC concentration of HDL remains low to
facilitate cholesterol efflux from tissues
Nascent HDL gradually becomes rich in
CE & converted to spherical HDL3

 Further modification of HDL3 & synthesis
of HDL2:
HDL3 continues further uptake of
cholesterol from peripheral cells
 Subsequently, HDL3 transfers part of its CE
to other circulating apo B containing LPs
(CM, VLDL, IDL, LDL) in exchange of
TAG & FC from them. The exchange is
mediated by CETP (Cholesterol ester
transfer protein)
HDL3 gets even larger & becomes HDL2
(mature HDL)

 Clearance of mature HDL (HDL2):
HDL2 goes to liver & binds with hepatocytes
where HDL off-loads cholesterol. Disposal of
off-loaded cholesterol from hepatocyte by 3
mechanisms:
Excretion with bile as FC
Conversion to bile acid & then excretion
with bile
Repackaged in to VLDL & then secretion
into blood

 Some of the HDL2 after having their
cholesterol off-loaded, is subjected to
hepatic lipase (HL) present in hepatic
sinusoidal endothelium. HL hydrolyzes the
TAG & PL of HDL2 and converts HDL2
again into HDL3 particles.
Later on these particles join with the newly
formed nascent hepatic HDL and return to
plasma to participate in the next cycle of the
cholesterol excretion from peripheral
tissues. This interchange of HDL2 & HDL3
is known as ”HDL cycle”.

HDL Metabolism
PC = Phosphatidylcholine/Lecithin

 Cyclical repetition of cholesterol
extraction from peripheral tissues &
sending it to liver through HDL activity.
Nascent HDL released from liver picks up
cholesterol from peripheral tissues and
converts to HDL3
HDL3 again picks up cholesterol from
peripheral tissues , exchanges lipids with
other circulating apo B containing LPs and
matures to HDL2

HDL2 comes back to liver to off-load
cholesterol. In liver, some of the HDL2 , after
releasing cholesterol, is assaulted by hepatic
lipase (HP). HL hydrolyzes TAG & PL of
HDL2 and turns it again into lipid depleted
HDL3
HDL3 along with other newly produced
hepatic nascent HDL repeats the process of
cholesterol extraction from peripheral tissues

Removal of cholesterol from peripheral
tissues back to liver mediated by HDL cycle.

 From liver, cholesterol is deposited to
peripheral tissues through VLDL-IDL-LDL
cascade pathway.
 By RCT, cholesterol is picked up by HDL
from peripheral tissues & sent back to liver
for excretion and other purposes. This is
carried out via two major routes:
 Direct route: HDL picks up cholesterol
from peripheral tissues & directly go to liver
to deliver cholesterol

Indirect route: HDL picks up cholesterol
from peripheral tissues & transfer it to
other apo B containing LPs (CM, VLDL,
IDL, LDL), mediated by CETP. These
LPs later on deliver cholesterol to liver.

Factors facilitating RCT:
HDL receptors on peripheral tissues/
hepatocytes
 Apo A
 LCAT
 CETP
HL

Importance of RCT:
RCT mediate by HDL activity facilitates
cholesterol excretion from body. This keeps the
serum cholesterol normal , thus reduces the
risk of IHD & other atherosclerotic diseases.

Chylomicrons is
a transporter of
dietary lipids
whereas VLDL is a
transporter of
endogenous
lipids(mainly TGs).
 LDL transports
cholesterol to
peripheral cells
while HDL
transports
cholesterol from
peripheral cells
back to liver.

 Atherosclerosis and hypertension
 Coronary heart diseases
 Lipoproteinemias (hypo and hyper)
 Fatty liver

Lipoproteins: Structure, classification, metabolism and significance

Lipoproteins: Structure, classification, metabolism and significance

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