Download MBBS Biochemistry PPT 72 Lipoprotein Metabolism Lecture Notes

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Formation,Functions,Utilization

Of

Lipoproteins

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In

Health And Disease
In Human Body

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How Transportation Of Lipids

Occur

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Through Aqueous Media ?



What are Lipoproteins ?

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? Lipoproteins are

complex

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macromolecules

? Biosynthesized by

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aggregation of

Lipids and

Apoproteins.

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? Lipoproteins are compound

Lipids/Conjugated Proteins.

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? Lipoproteins acquire charge and

made soluble in aqueous phase.
Why Lipoproteins are Biosynthesized?

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Al types of Lipoproteins are

Biosynthesized In Human body

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vNeutral Lipid

(Nonpolar)Biomolecules: Relatively

insoluble in water

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vTherefore, Lipids are transported

in plasma and Lymph (aqueous

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phase) as Lipoproteins

Hydrophobic lipids

Amphiphilic lipids

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Structure Of Lipoprotein

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Structure of lipoprotein



Hydrophobic lipids (TAG, CE) in Core

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Amphiphilic lipids (C, PL) and proteins on

surface

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Plasma Lipoproteins (Structure)

? Non-covalent

assemblies of lipids

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and proteins

? LP core

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? Triglycerides
? Cholesterol esters

? LP surface

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? Phospholipids
? Proteins

Function as transport vehicles

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? Cholesterol

for triacylglycerols and

cholesterol in the blood

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Contents Of Lipoproteins Structure

?Non polar Lipids are at

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center

?Polar Lipids and

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Apoproteins are present

at periphery.

Function/Role Of Lipoproteins

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Serves As Vehicles Of Lipid Transport

Through Aqueous Phase
?Lipoproteins function

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as transport vehicles

?For transportation of

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insoluble form of

Lipids in blood plasma.

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? Lipoproteins deliver lipid

forms (Cholesterol and TAG

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etc) from one tissue to

various other tissues for

their utilization.

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? Various Lipoproteins formed within

body cells

? Serves in transportation of

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? Exogenous (Dietary Source)
? Endogenous (Lipids biosynthesized)
? From one organ to another through

aqueous phase of Lymph and blood.

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Role of Lipoproteins Components

?Substrates for Energy Metabolism (TAG)
?Provide Essential components for cell

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structure (PL, Cholesterol)

?Precursors for Hormones (Cholesterol)
?Precursors for Bile acids and Bile salts (C)

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?Carries Lipid soluble Vitamins
Types Of Lipoproteins

? There are different types of Lipoproteins

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depending upon:

I. Site of Lipoprotein Biosynthesis
I . Lipid Content of LPL
I I. Apoprotein Type and Content

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IV. Diameter /Size of LPL
V. Transport Destination
VI. Ultracentrifugation
VI .Electrophoretic Pattern
Lipoproteins

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Site Of

Destination

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Major

Biochemical

Synthesis

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Lipids

Functions

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Chylomicrons Intestine Liver

Exogenous

Deliver lipids of

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Triacylglycerol

dietary origin to

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Liver and

Adiposecytes

VLDLs

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Liver

Extra Hepatic

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Endogenous

Deliver

Tissues

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Triacylglycerol

endogenously

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produced Lipids

to

Extrahepatocytes

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LDLs

Intravascular Extra hepatic

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Cholesterol

Deliver

by removal of Tissues

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endogenously

Triacylglycerol

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produced

from VLDL

cholesterol to

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Extrahepatocytes

HDLs

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Liver and

Liver and steroid Phospholipid

Remove and

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intestine

-hormone-

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Cholesterol

degrade

producing glands

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Cholesterol.


Chylomicrons

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Very low density

Lipoprotein (VLDL)

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Low density

Lipoprotein (LDL)

High density

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Lipoprotein (HDL)
Lipoproteins

Lipoprotein Nomenclature, Composition and

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Separation

CM

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VLDL

LDL

HDL

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Major ApoB 48 ApoB 100 ApoB 100 ApoA-I

Protein

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Major TAG

TAG CE

PL

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and CE

Lipid

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Ultracentrifugation

of

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Lipoproteins


Lipoprotein

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Particles with distinct densities

1.Electrophoresis

2. Ultra centrifugation method

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method:

CM (chylomicron )

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CM (chylomicron)

Slow

very low density lipoprotein (

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Slow

VLDL)

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-Lipoprotein

low density lipoprotein ( LDL)

pre -Lipoprotein

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high density lipoprotein (HDL)

Fast

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High

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- Lipoprotein


Lipoprotein Electrophoresis

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Plasma Lipoproteins

For Triacylglycerol Transport (TAG-rich):

- Chylomicrons: TAG of dietary origin

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- VLDL:TAG of Endogenous (hepatic)

synthesis

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For Cholesterol transport (cholesterol-rich):

LDL: Mainly Free Cholesterol

HDL: Mainly esterified Cholesterol

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Features Of Lipoprotein Metabolism
Important Organs Involved

In LPL Metabolism

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? Intestine
? Liver
? Extra hepatocytes
? Adipose Cytes

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Lipoprotein Metabolism

? Highly Complex
? Specific

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? Highly Dynamic
? Regulated
? Wel Communicated, Coordinated

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Lipoproteins In Health

Are In Dynamic State

? Biosynthesized at specific sites

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? Components of Lipoproteins are responsible for its

metabolism

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? Mobilized out from cel s /organs

? Modified in Blood circulation

? Interrelated with one another

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? Uptake Specific dependent on specific receptor and

transporters

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? Receptor mediated endocytosis

? Utilized and Assimilated to very great extent

? Highly Coordinated and Regulated

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Important Enzymes and

Proteins

Involved in

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Lipoprotein Metabolism

? Lipoprotein Lipase (LPL)
? Hepatic Lipase/HTGL

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? LCAT
? CETP
? Apoproteins
? Transporters
? Receptors

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Lipoprotein Lipase

OR

A Clearing Factor

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Lipoprotein Lipase (LPL)

LPL is located in

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?
endothelial lining of

blood vessels.
Lipoprotein Lipase (LPL)

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? LPL is an extracel ular enzyme,

anchored by Heparan sulfate to

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capil ary wal s of most tissues

? It is predominantly present in

Adipose tissue, Cardiac & Skeletal

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muscle

? LPL requires Apo C-II for its activation

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? LPL degrades TAG into Glycerol and free

fatty acids by its activity.

? Insulin stimulates its synthesis and

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transfer to luminal surface of capil ary.
Lipoprotein Lipases

? Lipoprotein Lipases in capil aries of

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adipose and muscle tissues hydrolyze

TAG in VLDLs.

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? VLDLs become IDLs
? IDLs looses more TAG and become LDLs.
? LDLs are less in TAG and rich in

Cholesterol and Cholesterol-esters.

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? Lipoprotein Lipase act upon TAG

of Lipoproteins and hydrolyze it

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? LPL Transforms ?

?Chylomicron to Chylomicron

remnant

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?VLDL to LDL


? Thus LPL clear circulating

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Lipoproteins from blood

hence it is termed as

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Clearing Factor.
? Type I Hypolipoproteinemia
? This is termed as Familial

Lipoprotein Lipase deficiency

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? Caused due to:

?LPL defect
?Apo C-I defect

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? LPL Hydrolyzes Triacylglycerol (TAG)

in core of CM and VLDL to free Fatty

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acids and Glycerol.

? Released free fatty acids and Glycerol
? Then enter into the tissue, mainly

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adipose, heart, and muscle (80%),

while about 20% goes indirectly to the

Liver.

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LPL Mediates

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Fatty Acid Uptake By Adiposecytes



Hepatic Lipase (HL)

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Hepatic Triglyceride Lipase (HTGL)

? HL is bound to the surface of Liver

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cells
? Hydrolyzes TAG to free fatty acids

and Glycerol
?HL is concerned with TAG hydrolysis

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in Chylomicron remnants and HDL

coming to Liver.

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LCAT

(Lecithin Cholesterol Acyltransferase)

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Formation of Cholesterol Esters in Lipoproteins

? LCAT is associated with HDL

Lipoprotein.

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? LCAT esterifies Cholesterol and

add to nascent HDL and form

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mature HDL.


CETP

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(Cholesteryl Ester Transfer Protein)

Cholesterol Ester Transfer Protein

CETP

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? CETP is also termed as plasma

lipid transfer protein.

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? CETP exchanges Lipids from

one Lipoprotein to another.

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CETP Activity

? CETP is a Plasma Protein that

facilitates transfer/exchange of

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? Cholesteryl Esters and

Triacylglycerol between two

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Lipoproteins.
?By CETP activity

Cholesteryl Ester May be

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transferred from HDL to:

? VLDL
? IDL

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? LDL

? CETP transfers TAG from VLDL or LDL

to HDL

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? In exchange of Cholesteryl Esters

from HDL to VLDL.
? HDL either transfers Cholesterol &

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Cholesterol esters.

? To Liver and extrahepatocytes by means

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of CETP activity.

CETP activity Responsible For

Sub fractions Of HDL

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HDL2 and HDL3


CETP by its activity

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Transforms HDL

HDL 3 to HDL 2

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?Prior to CETP activity HDL is

smaller particle termed as

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HDL3

? Post CETP activity HDL3

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become larger TAG rich and

termed as HDL2

?HDL 3 is Cholesteryl

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Ester rich biomolecule.

?HDL 2 is TAG and CE

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containing.
? Receptors Scavenger Receptor

Class B1 (SR-B1/SCARB1)

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present on Hepatocytes and

other organs are for HDL 2.

? HDL 2 is internalized in

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hepatocytes and components of

it get metabolized.

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Significance Of CETP Activity
CETP Activity

? Modifies HDL to its subtractions

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? Exchange and Utilizes Lipoprotein components
to its best without waste.

? Regulates and Internalizes HDL

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? Significance of CETP activity is to

transfer

? Valuable functional compound

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Cholesterol from HDL to VLDL and get

transported to extrahepatocytes when

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it is required for its use.

? Hence CETP activity is induced when

there is need of Cholesterol to Extra

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hepatocytes.
?CETP activity reduces

content of Cholesteryl

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Ester of HDL.

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CETP and LCAT are Interrelated

? Low Cholesterol Ester content

of HDL after CETP activity

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? Increases HDL associated LCAT

activity.

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Inhibition Of CETP Activity

Causes High HDL levels In

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Blood Circulation


? Effects of Inhibition of CETP

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? CETP will not transfer the HDL Cholesteryl

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Ester to VLDL, for use by extra hepatocytes.

? Not modify HDL3 to HDL2
? No internalization of HDL3 by Hepatocytes.
? This may elevate levels of HDL3 in blood.

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? Defective Scavenging role of HDL
? Leading to its bad consequences of

Atherosclerosis.
? Inhibition of CETP increases HDL3

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levels.

? But highly reduced CETP activity

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accelerates very high HDL3 levels.

? This abnormal high levels of HDL3

evidenced showing development of

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Atherosclerosis and Coronary Heart

Diseases.

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?Recent Studies have

evidenced

?CETP inhibiting drugs

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?Elevates levels of HDL3
?Increases mortality rate.
Failure of CETP Inhibitor Drugs

? Torcetrapib, failed in 2006 due to excess

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deaths in Phase II clinical trials.

? Dalcetrapib, development halted in May 2012

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when Phase II trials failed to show clinically

meaningful efficacy.

? Evacetrapib, development discontinued in

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2015 due to insufficient efficacy.

? Obicetrapib (TA-8995, AMG-899), Phase II

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results reported in 2015, discontinued in 2017

Apolipoproteins
Functions of

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Apolipoproteins

? Apoproteins are protein parts of

Lipoprotein structure

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? Apoproteins act as structural

components of Lipoproteins
?Apoproteins are polar moieties

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which impart solubility to

Lipoprotein structure.
? Functions Of Apoproteins

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? Recognizes Lipoprotein

receptors on cell membrane

surface as ligand.

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? Which further facilitates

uptake of LP by specific tissues.

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Apoproteins Activate /Inhibit

Enzymes Involved

in Lipoprotein Metabolism.

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? Apo A I, C I, A-IV : Activators of LCAT

? Apo C-II: Activator of LPL

? Apo C-III: Inhibitor of LPL

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? Apo AII: Inhibitor of Hepatic Lipase (HL)


? Chylomicrons contain ApoB-48.

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? VLDLs, IDLs and LDLs has ApoB-100.
HDL transfers

Apo E & Apo CII

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to

Chylomicrons & VLDL

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Different Lipoprotein Metabolism

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Chylomicron

Metabolism

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Metabolism of Chylomicrons

Surface Monolayer

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Phospholipids

Free Cholesterol

Protein

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Hydrophobic Core

Triglyceride

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Cholesteryl Esters


Chylomicron Metabolism

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Chylomicron Transport and Uptake


Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; , apolipoprotein C; E, apolipoprotein E;

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HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP,

LDL receptor-related protein.) Only the predominant lipids are shown.
Chylomicrons

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? Assembled in intestinal mucosal

cel s

? Has lowest density

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? It has largest size
? Highest % of lipids and lowest %

proteins

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? Highest concentration of

Triacylglycerol (dietary origin)

? Chylomicrons carry dietary lipids

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from intestine to Liver

? Responsible for physiological milky

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appearance of plasma (up to 2

hours after meal)
? Chylomicron is a type of

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Lipoprotein

? Formed in the intestinal

mucosal cells

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? Due to aggregation of

dietary digested and

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absorbed Lipids.

? The Chylomicrons has 99%

Lipids and 1% Proteins

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? The predominant Lipid present

in Chylomicrons is

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Triacylglycerol (TAG) of dietary

origin.
? The Apoprotein of Chylomicron is

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B48

? Significant role of Chylomicron is

to transport dietary Lipids from

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intestinal mucosal cell to Liver via

Lymph and Blood.

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? Chylomicrons formed in

intestinal mucosal cells are

? First released in lymphatic

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system

? Which then enters systemic

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blood circulation via thoracic

duct.
? Chylomicrons in blood circulation are not

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moved inertly

? But receives Apo C I and Apo E from the

circulating HDL and gets mature.

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? Apo C I then stimulates the enzyme

Lipoprotein Lipase present in endothelial

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lining of blood vessels of Adipose tissue

and Cardiac tissue.

? Activated Lipoprotein Lipase acts upon

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TAG of Chylomicrons ,

? Hydrolyze it into free fatty acids and

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Glycerol ,which then enters to

adjacent adiposecytes.

? Entered Free fatty acids TAG and

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stored as reserve food material.
? The circulating Chylomicrons

are continuously acted upon by

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Lipoprotein Lipase

? Most of the TAG is removed

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from it and transformed to

Chylomicron remnant till they

reach Liver.

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? The Liver has receptors for

Chylomicron remnant.

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? Chylomicron remnant linked to

receptors of hepatocytes are

internalized and metabolized in

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Liver.


? Chylomicrons transport dietary TAG

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and Cholesterol from the intestine to

the peripheral tissues

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? Lipoprotein lipase (LPL) is

activated by Apo C-II

? After most of the TG is removed,

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Chylomicrons become

Chylomicron remnants. During

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the process, CM give ApoC and

ApoA back to HDL
?CM remnants bind to specific

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receptors on the surface of liver

cells through apo E and then the

complex is Endocytosed.

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?Remnant receptor or ApoE

receptor or LRP (LDL receptor-

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related protein)


? Chylomicron remnants deliver

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dietary cholesterol and some

cellular cholesterol (via HDL)

to the liver.

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? Half life of CM is short, less

than 1 hour.
Chylomicrons

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Nascent Chylomicron are formed in the intestinal and

consists of rich in dietary TG + minimal amount of

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dietary cholesterol + Apo (B-48)

Mature Chylomicron after Nascent chylomicron

passage to blood, addition of Apo C II and Apo E from

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HDL

Lipoprotein lipase hydrolyzes TAG present in

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Chylomicrons

Chylomicron remnant taken up by the liver through

endocytosis.

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Apo C removed and returns back to HDL


Metabolism of VLDL and LDL

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Formation and Fate Of VLDL


VLDL Metabolism

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? The Lipoprotein Very Low

Density Lipoprotein (VLDL)

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? Biosynthesized in

Hepatocytes and Intestinal

Mucosal Cells.

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?The endogenously

biosynthesized Lipids are

aggregated

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?Along with Apoprotein B-

100 to form VLDL.

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? VLDL predominantly

contains Triacylglycerol of

endogenous origin.

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Role Of VLDL

? VLDL facilitates in mobilizing out the

endogenously synthesized Lipids in

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Hepatocytes and Intestinal mucosal cells.

? VLDL transports endogenous Lipids

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from Liver to Extra Hepatocytes via

blood.

?Nascent VLDL accepts Apo

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CII and Apo E from HDL

?This modify it to mature

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VLDLs in blood.
? Nascent VLDL: contains Apo B-100
? Mature VLDL: Apo B-100 plus

Apo C-II and Apo E

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(from HDL)

? Apo C-I is required for activation of

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Lipoprotein lipase

? Lipoprotein lipase is required to

degrade VLDL TAG into Glycerol and

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fatty acids
?Circulating VLDL on

action by Lipoprotein

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Lipase hydrolyzes most

of its TAG.

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?VLDL gets modified to

IDL and LDL.

? Thus intermediate product of

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IDL and end product LDL are

formed from VLDL

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? In blood circulation by action

of LPL on VLDL and removal of

TAG from it.

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Normal VLDL Metabolism

Prevents the person

to

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Suffer from Fatty Liver

? VLDL help in mobilizing out the

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endogenously biosynthesized Lipids

of Hepatocytes.

? Normal Formation and mobilization

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of VLDL prevents from accumulation

of excess Fat in the Liver and

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develop Fatty Liver.


Modifications of Circulating VLDLs

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VLDL IDL (returns Apo E to HDL) LDL

VLDL Metabolism

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Dietary Carbohydrate Increases

VLDL Production

Plasma

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Triglyceride

Dietary

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(VLDL)

Carbohydrate

VLDL Remnants

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IDL and LDL

? LDL results from loss of TAG in

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VLDL

? LDL contains relatively more

Cholesterol esters

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? LDL looses all Apo lipoproteins

except ApoB100.
Very Low Density Lipoprotein (VLDL)

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Nascent VLDLare formed in the liver and consists of

endogenous TG + 17 % cholesterol + Apo (B-100)

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Mature VLDL after Nascent VLDL passage to

blood, addition of ApoC II, ApoE and cholesterol

esters from HDL

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Lipoprotein lipase (LPL) hydrolyzes TAG present

in VLDL

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VLDL remnant containing less of TG and more of

cholesterol and taken up by the liver through

endocytosis.

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Apo C removed and returns to HDL


LDL Metabolism

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Most core lipid in LDL is Cholesterol ester.
ApoB100 is only Apolipoprotein in the surface.

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Formation and Fate Of LDL
? Low Density Lipoprotein (LDL) is a

Lipoprotein formed from VLDL in

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blood circulation.

? VLDL in blood circulation

receives Apo CII and Apo E from

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the circulating HDL.

? Apo CI then stimulates the

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Lipoprotein Lipase enzyme

present in the endothelial lining

of blood vessels.

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? Lipoprotein Lipase then acts upon

TAG present in VLDL ,hydrolyze it

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to Glycerol and free fatty acids
?LDL is the modified

form of VLDL formed

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in blood circulation.

?LDL is remnant of

VLDL

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?LDL is mostly associated

with Cholesterol and

Phospholipids with

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minimal TAG

?Of endogenous origin

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mobilized out from Liver.

? The major Apoproteins of LDL

is Apo B100

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? Same as VLDL since LDL is

derived from VLDL
? Function of LDL is to transport

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endogenously biosynthesized

Cholesterol from Liver to the

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peripheral /extrahepatic tissues.

LDL Receptor

? Cell surface protein

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? Recognizes Apolipoprotein B-100, present in VLDL,

IDL, LDL, and probably Apo-E

? LDL receptor is an integral membrane protein of

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115 kDa,

? LDL receptor is highly regulated
? Intracellular cholesterol concentration increases,

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the LDL receptor production is inhibited
LDL Receptor

?LDL receptor is also named

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as ApoB100/ApoE

receptors

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?Since ApoB-100 of LDL

binds to LDL receptor.

?The complexes of LDL and

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receptor are taken into the

cells by endocytosis,

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?Where LDL is degraded but

the receptors are recycled

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? LDL receptors are found on cel

surface of many cel types of

extrahepatocytes.

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? LDL is internalized by the tissues

when LDL get fixed to the LDL

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receptors.

? LDL receptor mediates

delivery of Cholesterol

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? By inducing endocytosis

and fusion with Lysosomes.

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? Lysosomal lipases and

proteases degrade the LDL.

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? Cholesterol then incorporates

into cell membranes or is

stored as cholesterol-esters of

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extrahepatocytes.


LDL Receptor

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LDL-Receptor-Related Protein-Associated

Protein (LRPAP1)

? Chaperone Protein which in humans is encoded

--- Content provided by⁠ FirstRanker.com ---

by LRPAP1 gene.

? Involved with trafficking of certain members of

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LDL receptor family including LRP1 and LRP 2

? Acts to inhibit binding of all known ligands for

these receptors

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? Prevent receptor aggregation and degradation in

endoplasmic reticulum, thereby acting as a

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molecular chaperone.

Mutations and diseases related to

LRPAP1

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? Abnormal ECM remodeling in neurons,

eye

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?Dementia
?Myopia
?Marfans Syndrome
LDL Cholesterol levels

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are

positively related to risk

of Cardiovascular

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Disease.

?LDL values within

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normal range is an

indication of healthy

status.

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?But the high LDL levels

are abnormal .
? Cholesterol associated to this

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high levels of LDL molecules

increases risk of

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Atherosclerosis and CVD.


? Hence this LDL associated

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Cholesterol is termed as "bad

Cholesterol"

Defect/Absence of

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LDL Receptors

Leads to Accumulation of LDL

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in Blood Circulation

Causing

Hypercholesteremia

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and

Atherosclerosis
? Defect in LDL receptors on tissues

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impairs LDL metabolism.

? Decreases LDL internalization

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within the tissues.

? Increases abnormal levels of LDL in

blood (< 130 mg%).

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? Increased LDL levels in

blood circulation due to

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defect in LDL receptors is

termed as Type I a

Hyperlipoproteinemia.

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? The major form of Lipid associated with LDL

is Cholesterol .

? Hence increased LDL levels is characterized

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by Hypercholesterolemia.

? The Cholesterol associated with elevated

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levels of LDL (more than its normal range) is

termed as bad Cholesterol,

? Since it increases the risk of Atherosclerosis

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and its complications .

? Persons lacking the LDL

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receptor suffer from Familial

Hypercholesteremia

? Due to result of a mutation in

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a single autosomal gene

? Total plasma cholesterol and

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LDL levels are elevated.
?Cholesterol Levels of:

?Healthy person = < 200 mg/dl

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?Heterozygous individuals = 300 mg/dl



?Homozygous individuals = 680 mg/dl

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High LDL levels can lead to

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Cardiovascular Disease
Most Homozygous individuals

die of cardiovascular disease

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in childhood

? LDL can be oxidized to form

oxidized LDL

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? Oxidized LDL is taken up by

immune cells cal ed

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macrophages.

? Macrophages become

engorged to form foam cells.

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? Foam cel s become trapped in

the wal s of blood vessels and

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contribute to the formation of

atherosclerotic plaques.

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? Causes narrowing of the

arteries which can lead to

MI/heart attacks.

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Familial hypercholesterolemia is due to a gene

defect in the LDL receptor

? Michael Palmer 2014

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Role Of HDL

Reverse Transport Of

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Cholesterol


? HDL is a high density

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Lipoprotein.

? Nascent HDL is biosynthesized

in Liver.

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? It is reservoir of Apoproteins

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? HDL is the Lipoprotein, with highest

density.

? Since it is associated with 40-50% of

--- Content provided by‌ FirstRanker.com ---

Apoproteins.

? The Apoproteins of HDL are Apo A I,

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Apo A I , Apo C I,C I , Apo D and Apo E.

? HDL serves as a reservoir of

Apoprotein during its circulation.

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? HDL gives it Apo CII and Apo E to

circulating nascent Chylomicrons

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and VLDL .
? Nascent HDL of discoid shaped

(Empty Bag) biosynthesized in

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Liver

? It is released in the blood

circulation for scavenging action.

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The HDL has Scavenging Action

It serves as a

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Scavenger For

Unwanted Body Lipids
? The Enzyme Lecithin Cholesterol Acyl

--- Content provided by⁠ FirstRanker.com ---

Transferase (LCAT) is associated with HDL

metabolism.

? Apo A I,A IV and CI stimulates the LCAT

--- Content provided by FirstRanker.com ---

activity of HDL.

? LCAT by its activity help in esterification of

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free Cholesterol to Esterified

Cholesterol/Cholesterol Ester.

? HDL by its scavenging action collects the extra

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non functional Cholesterol lying in blood

vessels and peripheral tissues.

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? HDL esterifies Choleserol by its LCAT activity

and to HDL bag.

? The nascent HDL bags changes to spherical

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shape .

? HDL is more associated with Phospholipids

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and Cholesterol.
? The receptors for HDL are

present on Liver cells.

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? HDL transports the excess,

unused Lipids from extra

hepatic tissues back to Liver for

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its metabolism and excretion.

? The role of HDL is opposite to LDL.

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? HDL transports Cholesterol From

extra hepatic tissues back to Liver.

? Thus the role of HDL is termed as

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reverse transport of Cholesterol.
? Normal serum HDL levels are 30-60

mg%.

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? The efficient activity of HDL is good

to the body

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? As it prevents risk of Atherosclerosis

and their complications.

Reverse Cholesterol Transport (RCT)

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High Density Lipoproteins (HDL ? Good)

? CETP by its activity modifies HDL 3

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to HDL 2.

? HDL2 is then get internalized in

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Hepatocytes for its final use.

? Cholesterol Ester carried by HDL to

hepatocytes is degraded to Bile

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acids and Bile salts and get excreted

out.
Fate of HDL

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HDL 2 binds SR-B1 receptor on Hepatocytes

And Other Cel s

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Transfers Cholesterol &

Cholesterol ester to cell

Depleted HDL dissociates

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& re-enters circulation

? HDL can bind to specific

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hepatic receptors SR-B1

? But primary HDL clearance

occurs through uptake by

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scavenger receptor SR-B1.
? SR-B1 can be upregulated in cells

when Cholesterol levels are low in

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hepatic cells.

? SR-B1 is down regulated when

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cholesterol levels are high in cells.

? Defect in low HDL synthesis in Liver

lowers the HDL activity and increases

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the risk of Atherosclerosis.

? Defect in HDL receptors on Liver may

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abnormally increase the HDL levels in

blood circulation and also increases the

risk of Atherosclerosis.

--- Content provided by‍ FirstRanker.com ---

The Lecithin-Cholesterol Acyltransferase (LCAT)

reaction

Cholesterol esters can be stored inside lipoprotein

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particles
HDL Interactions

with Other Particles

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Tangier Disease: Disruption of Cholesterol

Transfer to HDL

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? Michael Palmer 2014


HDL and Reverse Cholesterol Transport

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Tangier Disease

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--- Content provided by FirstRanker.com ---

LDL-R

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LDL-R

50% of HDL C may

Return to the liver

--- Content provided by‍ FirstRanker.com ---

On LDL via CETP

LDL/HDL Ratio and Cardiovascular Disease

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? LDL/HDL ratios are used as a

diagnostic tool for signs of

Cardiovascular disease

--- Content provided by‍ FirstRanker.com ---

? A good LDL/HDL ratio is 3.5
?LDL above normal range =
"Bad Cholesterol"

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?HDL within normal range =
"Good Cholesterol"
-HDL above normal range =
"Bad Cholesterol"

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? Protective role of HDL is not very

clear.

?An esterase that breaks down

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oxidized lipids is associated with

HDL.

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?It is possible (but not proven) that

this enzyme helps to destroy

oxidized LDL

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Lipoproteins Facilitate Lipid

Transport

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Effects Of Normal

Lipoprotein Metabolism

Normal LP Metabolism

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? Maintains Normal levels of Lipoproteins

in the blood circulation by:

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?Normal Formation of LP by specific tissues

?Normal Transformation and Transport of

LP in blood

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?Normal Uptake of LP by specific tissues
? Normal Lipoprotein

Metabolism Reduces the risk

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of:

?Atherosclerosis

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?Myocardial Infarction

?Stroke

Lipoprotein Population Distributions

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? Serum Lipoprotein

concentrations differ between

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adult men and women.

? Primarily as a result of

differences in sex hormone

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levels.


? Women having, on average, higher HDL

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cholesterol levels and lower total

Cholesterol and TAG levels than men.

--- Content provided by FirstRanker.com ---

? The difference in total cholesterol,

however, disappears in post

menopause as Estrogen decreases and

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use of Cholesterol is reduced.

--- Content provided by​ FirstRanker.com ---

PCSK9

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Proprotein Convertase Subtilisin /Kexin type 9
PCSK9 - Mechanisms of Action

? PCSK9 is a Proprotein Convertase responsible for

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? Degradation of low-density lipoprotein (LDL) receptors in

Liver.

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? Mutations in PCSK9 gene cause familial

Hypercholesterolemia

? Due to reduced number of LDL receptors on surface of

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hepatocytes.

? Decreases their ability to clear LDL cholesterol from plasma.

--- Content provided by‍ FirstRanker.com ---

PCSK9 inhibitors ? Mechanisms of Action

? Conversely other PCSK9 mutations result in
? Unusually low concentrations of plasma LDL

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cholesterol and a reduced risk of atherosclerotic

disease.

? Blocking activity of PCSK9 with monoclonal

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antibodies reduces degradation of LDL receptors

? An injection of PCSK9-specific antibody

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suppresses LDL-cholesterol concentrations.

? Increases clearance of LDL cholesterol

--- Content provided by⁠ FirstRanker.com ---