LDL & HDL METABOLISM

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.

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.

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.

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

LDL & HDL METABOLISM

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LDL & HDL METABOLISM