Gandham.

Rajeev
Email:gandhamrajeev33@gmail.com
 LDL Metabolism

LDL is bad-cholesterol.
It transports cholesterol from liver to
peripheral tissues.
LDL contains only one lipoprotein Apo B-100.
LDL particles are derived from VLDL.
Small part is directly released from liver.
Half-life is 2 days.
Structure of LDL
 Metabolism
LDL is taken up by peripheral tissues by
receptor-mediated endocytosis.
LDL receptors are present in all tissues.
But most abundant in hepatic cells.
LDL receptors located in specialized regions
called clathrin-coated pits.
Binding of LDL to receptor is by apo-B-100.
It is highly regulated.
 LDL Receptors

It is a polypeptide, consists of 839 amino acids.

Contains extracellular & intracellular domains.
Extracellular domain is responsible for
binding of apo-B-100 & apo-E.
Intracellular domain is responsible for the
clustering of LDL receptors into regions of
plasma membrane termed coated pits.
 Apo-B-100 binds to apo-B-100 receptor,
receptor LDL complex is internalized by
endocytosis.
The endosome vesicles fuses with
lysosomes.
The receptor is recycles & returned to the
cell surface.
 LDL particles, apoproteins & cholesterol
esters are hydrolyzed by hydrolases,
forming free amino acids & free
cholesterol.
70% of LDL is degraded in the liver &
remaining is in extra-hepatic tissues.
Free cholesterol incorporated into
plasma membrane or stored in cells.
Uptake & fate of LDL
 Functions of LDL
75% of plasma cholesterol is incorporated into
LDL particles.
LDL transports cholesterol from liver to
peripheral tissues.
The transported cholesterol has following fates:
For synthesis of steroids.
May be incorporated into membranes.
May be esterified to MUFA & stored.
Forward & reverse transport of cholesterol
 LDL & its clinical significance

LDL concentration is increased in

cardiovascular diseases.
Small fraction of cholesterol is taken up
by macrophages.
Increased levels of LDL or modified LDL or
oxidized LDL increases the fraction of
cholesterol taken by macrophages.
 There is an LDL infiltration through arterial
walls & taken up by macrophages or
scavenger cells.
This is starting event of atherosclerosis,
leading to MI.
These cells become engorged with
cholesterol, foam cells are formed.
 These are deposited in sub-endothelial
space triggering the formation of
atheromatous plaque.
Leads to thrombosis & coronary artery
disease.
LDL is a bad-cholesterol.
Defects in LDL receptor synthesis leads
to familial hypercholesterolemia.
 Lipoprotein (A)
Lp(a) is associated with myocardial
infarction & is called as little rascal
Lp(a) is attached to apo-B-100 by a disulfide
bond.
In 40% population, there is no detectable
level of Lp(a) in serum.
Lp(a) levels >30 mg/dl is susceptible for heart
attack at a younger age.
 Indians have higher levels of Lp(a) than
western populations.
Lp(a) interferes with plasminogen
activation & impairs fibrinolysis.
Leads to unopposed intravascular
thrombosis & possible myocardial
infarction.
 HDL Metabolism
HDL is a good cholesterol.
Transports cholesterol from peripheral tissues
to liver.
Synthesized in liver.
Major apoproteins in HDL are Apo A1, with
some Apo A2, Apo C & Apo E.
HDL is an plasma reservoir of Apo C & Apo E,
which can be transferred to VLDL &
chylomicrons.
 Metabolism
Intestinal cells synthesize components of
HDL & release into blood.
Nascent HDL are discoid in shape.
Free cholesterol is taken up by the HDL
Apo A-1 of HDL activates LCAT.
LCAT binds to HDL disc.
Cholesterol from cell is transferred to HDL
by cholesterol efflux regular protein, which
is an ABC protein.
 Lecithin is a component of lipid bilayer of
HDL disc.
Second carbon of lecithin contains PUFA.
This PUFA is transferred to 3rd OH group of
cholesterol to form cholesterol esters.
Cholesterol esters moves into the interior
of HDL disc.
HDL becomes spherical shape with lot of
cholesterol esters are formed.
This is called as HDL-3.
 Mature HDLs are taken up by liver cells by
apo A-1 mediated receptor mechanism.
HDL is taken up by hepatic scavenger
receptor B1.
Hepatic lipase hydrolyzes HDL
phospholipids & TAG, cholesterol esters are
released into liver cells.
These cholesterol esters are used for the
synthesis of bile acids or excreted as bile.
 When HDL3 remains in circulation,
cholesterol esters from HDL is
transferred to VLDL, IDL & LDL by a
cholesterol ester transfer protein (CETP).
TAG from VLDL,IDL & LDL is transferred
to HDL in exchange for cholesterol
esters.
 HDL particles rich in TAG & spherical are
called as HDl-2
These particles are first acted upon by
hepatic triglyceride lipase (HTGL)
Efflux of cholesterol from peripheral cells
to HDL is mediated by ABC transporter
protein.
HDL Metabolism
 Functions of HDL
HDL is the transports cholesterol from
peripheral tissues to liver, called as reverse
cholesterol transport.
Cholesterol is excreted through bile.
Cholesterol excretion needs prior
esterification with PUFA.
PUFA reduces serum cholesterol levels.
PUFA is anti-atherogenic.
 HDL & its clinical significance

Serum HDL levels are inversely related to

the incidence of MI.
HDL is anti-atherogenic or protective in
nature.
It is a good cholesterol.
HDL levels <35mg/dl increases risk,
>65mg/dl reduces the risk of CAD.
 Free fatty acids
Complexed with albumin in plasma.
FFA is derived from lipolysis of TAG stored in
adipose tissue by hormone sensitive lipase.
FFA may be long chain saturated or
unsaturated FA. & are transported to heart,
skeletal muscle, liver & other tissues.
FFA are either oxidized or incorporated into
tissue lipids.
 In tissue cells, FFA-albumin complex is
dissociated, FFA binds with fatty acid
transport protein.
It is a co-transport with sodium.
Half-life of FFA is 1-2 minutes.
During starvation, 40-50% of energy is met
by oxidation of FFA.
 References

Textbook of Biochemistry-U Satyanarayana

Textbook of Biochemistry-DM Vasudevan

Thank You