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

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