Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 72 Lipoprotein Metabolism Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
Lipoprotein Metabolism
Generation,Operation,Destruction
Formation,Functions,Utilization
Of
Lipoproteins
In
Health And Disease
In Human Body
How Transportation Of Lipids
Occur
Through Aqueous Media ?
What are Lipoproteins ?
? Lipoproteins are
complex
macromolecules
? Biosynthesized by
aggregation of
Lipids and
Apoproteins.
? Lipoproteins are compound
Lipids/Conjugated Proteins.
? Lipoproteins acquire charge and
made soluble in aqueous phase.
Why Lipoproteins are Biosynthesized?
Al types of Lipoproteins are
Biosynthesized In Human body
vNeutral Lipid
(Nonpolar)Biomolecules: Relatively
insoluble in water
vTherefore, Lipids are transported
in plasma and Lymph (aqueous
phase) as Lipoproteins
Hydrophobic lipids
Amphiphilic lipids
Structure Of Lipoprotein
Structure of lipoprotein
Hydrophobic lipids (TAG, CE) in Core
Amphiphilic lipids (C, PL) and proteins on
surface
Plasma Lipoproteins (Structure)
? Non-covalent
assemblies of lipids
and proteins
? LP core
? Triglycerides
? Cholesterol esters
? LP surface
? Phospholipids
? Proteins
Function as transport vehicles
? Cholesterol
for triacylglycerols and
cholesterol in the blood
Contents Of Lipoproteins Structure
?Non polar Lipids are at
center
?Polar Lipids and
Apoproteins are present
at periphery.
Function/Role Of Lipoproteins
Serves As Vehicles Of Lipid Transport
Through Aqueous Phase
?Lipoproteins function
as transport vehicles
?For transportation of
insoluble form of
Lipids in blood plasma.
? Lipoproteins deliver lipid
forms (Cholesterol and TAG
etc) from one tissue to
various other tissues for
their utilization.
? Various Lipoproteins formed within
body cells
? Serves in transportation of
? Exogenous (Dietary Source)
? Endogenous (Lipids biosynthesized)
? From one organ to another through
aqueous phase of Lymph and blood.
Role of Lipoproteins Components
?Substrates for Energy Metabolism (TAG)
?Provide Essential components for cell
structure (PL, Cholesterol)
?Precursors for Hormones (Cholesterol)
?Precursors for Bile acids and Bile salts (C)
?Carries Lipid soluble Vitamins
Types Of Lipoproteins
? There are different types of Lipoproteins
depending upon:
I. Site of Lipoprotein Biosynthesis
I . Lipid Content of LPL
I I. Apoprotein Type and Content
IV. Diameter /Size of LPL
V. Transport Destination
VI. Ultracentrifugation
VI .Electrophoretic Pattern
Lipoproteins
Site Of
Destination
Major
Biochemical
Synthesis
Lipids
Functions
Chylomicrons Intestine Liver
Exogenous
Deliver lipids of
Triacylglycerol
dietary origin to
Liver and
Adiposecytes
VLDLs
Liver
Extra Hepatic
Endogenous
Deliver
Tissues
Triacylglycerol
endogenously
produced Lipids
to
Extrahepatocytes
LDLs
Intravascular Extra hepatic
Cholesterol
Deliver
by removal of Tissues
endogenously
Triacylglycerol
produced
from VLDL
cholesterol to
Extrahepatocytes
HDLs
Liver and
Liver and steroid Phospholipid
Remove and
intestine
-hormone-
Cholesterol
degrade
producing glands
Cholesterol.
Chylomicrons
Very low density
Lipoprotein (VLDL)
Low density
Lipoprotein (LDL)
High density
Lipoprotein (HDL)
Lipoproteins
Lipoprotein Nomenclature, Composition and
Separation
CM
VLDL
LDL
HDL
Major ApoB 48 ApoB 100 ApoB 100 ApoA-I
Protein
Major TAG
TAG CE
PL
and CE
Lipid
Ultracentrifugation
of
Lipoproteins
Lipoprotein
Particles with distinct densities
1.Electrophoresis
2. Ultra centrifugation method
method:
CM (chylomicron )
CM (chylomicron)
Slow
very low density lipoprotein (
Slow
VLDL)
-Lipoprotein
low density lipoprotein ( LDL)
pre -Lipoprotein
high density lipoprotein (HDL)
Fast
High
- Lipoprotein
Lipoprotein Electrophoresis
Plasma Lipoproteins
For Triacylglycerol Transport (TAG-rich):
- Chylomicrons: TAG of dietary origin
- VLDL:TAG of Endogenous (hepatic)
synthesis
For Cholesterol transport (cholesterol-rich):
LDL: Mainly Free Cholesterol
HDL: Mainly esterified Cholesterol
Features Of Lipoprotein Metabolism
Important Organs Involved
In LPL Metabolism
? Intestine
? Liver
? Extra hepatocytes
? Adipose Cytes
Lipoprotein Metabolism
? Highly Complex
? Specific
? Highly Dynamic
? Regulated
? Wel Communicated, Coordinated
Lipoproteins In Health
Are In Dynamic State
? Biosynthesized at specific sites
? Components of Lipoproteins are responsible for its
metabolism
? Mobilized out from cel s /organs
? Modified in Blood circulation
? Interrelated with one another
? Uptake Specific dependent on specific receptor and
transporters
? Receptor mediated endocytosis
? Utilized and Assimilated to very great extent
? Highly Coordinated and Regulated
Important Enzymes and
Proteins
Involved in
Lipoprotein Metabolism
? Lipoprotein Lipase (LPL)
? Hepatic Lipase/HTGL
? LCAT
? CETP
? Apoproteins
? Transporters
? Receptors
Lipoprotein Lipase
OR
A Clearing Factor
Lipoprotein Lipase (LPL)
LPL is located in
?
endothelial lining of
blood vessels.
Lipoprotein Lipase (LPL)
? LPL is an extracel ular enzyme,
anchored by Heparan sulfate to
capil ary wal s of most tissues
? It is predominantly present in
Adipose tissue, Cardiac & Skeletal
muscle
? LPL requires Apo C-II for its activation
? LPL degrades TAG into Glycerol and free
fatty acids by its activity.
? Insulin stimulates its synthesis and
transfer to luminal surface of capil ary.
Lipoprotein Lipases
? Lipoprotein Lipases in capil aries of
adipose and muscle tissues hydrolyze
TAG in VLDLs.
? VLDLs become IDLs
? IDLs looses more TAG and become LDLs.
? LDLs are less in TAG and rich in
Cholesterol and Cholesterol-esters.
? Lipoprotein Lipase act upon TAG
of Lipoproteins and hydrolyze it
? LPL Transforms ?
?Chylomicron to Chylomicron
remnant
?VLDL to LDL
? Thus LPL clear circulating
Lipoproteins from blood
hence it is termed as
Clearing Factor.
? Type I Hypolipoproteinemia
? This is termed as Familial
Lipoprotein Lipase deficiency
? Caused due to:
?LPL defect
?Apo C-I defect
? LPL Hydrolyzes Triacylglycerol (TAG)
in core of CM and VLDL to free Fatty
acids and Glycerol.
? Released free fatty acids and Glycerol
? Then enter into the tissue, mainly
adipose, heart, and muscle (80%),
while about 20% goes indirectly to the
Liver.
LPL Mediates
Fatty Acid Uptake By Adiposecytes
Hepatic Lipase (HL)
Hepatic Triglyceride Lipase (HTGL)
? HL is bound to the surface of Liver
cells
? Hydrolyzes TAG to free fatty acids
and Glycerol
?HL is concerned with TAG hydrolysis
in Chylomicron remnants and HDL
coming to Liver.
LCAT
(Lecithin Cholesterol Acyltransferase)
Formation of Cholesterol Esters in Lipoproteins
? LCAT is associated with HDL
Lipoprotein.
? LCAT esterifies Cholesterol and
add to nascent HDL and form
mature HDL.
CETP
(Cholesteryl Ester Transfer Protein)
Cholesterol Ester Transfer Protein
CETP
? CETP is also termed as plasma
lipid transfer protein.
? CETP exchanges Lipids from
one Lipoprotein to another.
CETP Activity
? CETP is a Plasma Protein that
facilitates transfer/exchange of
? Cholesteryl Esters and
Triacylglycerol between two
Lipoproteins.
?By CETP activity
Cholesteryl Ester May be
transferred from HDL to:
? VLDL
? IDL
? LDL
? CETP transfers TAG from VLDL or LDL
to HDL
? In exchange of Cholesteryl Esters
from HDL to VLDL.
? HDL either transfers Cholesterol &
Cholesterol esters.
? To Liver and extrahepatocytes by means
of CETP activity.
CETP activity Responsible For
Sub fractions Of HDL
HDL2 and HDL3
CETP by its activity
Transforms HDL
HDL 3 to HDL 2
?Prior to CETP activity HDL is
smaller particle termed as
HDL3
? Post CETP activity HDL3
become larger TAG rich and
termed as HDL2
?HDL 3 is Cholesteryl
Ester rich biomolecule.
?HDL 2 is TAG and CE
containing.
? Receptors Scavenger Receptor
Class B1 (SR-B1/SCARB1)
present on Hepatocytes and
other organs are for HDL 2.
? HDL 2 is internalized in
hepatocytes and components of
it get metabolized.
Significance Of CETP Activity
CETP Activity
? Modifies HDL to its subtractions
? Exchange and Utilizes Lipoprotein components
to its best without waste.
? Regulates and Internalizes HDL
? Significance of CETP activity is to
transfer
? Valuable functional compound
Cholesterol from HDL to VLDL and get
transported to extrahepatocytes when
it is required for its use.
? Hence CETP activity is induced when
there is need of Cholesterol to Extra
hepatocytes.
?CETP activity reduces
content of Cholesteryl
Ester of HDL.
CETP and LCAT are Interrelated
? Low Cholesterol Ester content
of HDL after CETP activity
? Increases HDL associated LCAT
activity.
Inhibition Of CETP Activity
Causes High HDL levels In
Blood Circulation
? Effects of Inhibition of CETP
? CETP will not transfer the HDL Cholesteryl
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.
? Defective Scavenging role of HDL
? Leading to its bad consequences of
Atherosclerosis.
? Inhibition of CETP increases HDL3
levels.
? But highly reduced CETP activity
accelerates very high HDL3 levels.
? This abnormal high levels of HDL3
evidenced showing development of
Atherosclerosis and Coronary Heart
Diseases.
?Recent Studies have
evidenced
?CETP inhibiting drugs
?Elevates levels of HDL3
?Increases mortality rate.
Failure of CETP Inhibitor Drugs
? Torcetrapib, failed in 2006 due to excess
deaths in Phase II clinical trials.
? Dalcetrapib, development halted in May 2012
when Phase II trials failed to show clinically
meaningful efficacy.
? Evacetrapib, development discontinued in
2015 due to insufficient efficacy.
? Obicetrapib (TA-8995, AMG-899), Phase II
results reported in 2015, discontinued in 2017
Apolipoproteins
Functions of
Apolipoproteins
? Apoproteins are protein parts of
Lipoprotein structure
? Apoproteins act as structural
components of Lipoproteins
?Apoproteins are polar moieties
which impart solubility to
Lipoprotein structure.
? Functions Of Apoproteins
? Recognizes Lipoprotein
receptors on cell membrane
surface as ligand.
? Which further facilitates
uptake of LP by specific tissues.
Apoproteins Activate /Inhibit
Enzymes Involved
in Lipoprotein Metabolism.
? Apo A I, C I, A-IV : Activators of LCAT
? Apo C-II: Activator of LPL
? Apo C-III: Inhibitor of LPL
? Apo AII: Inhibitor of Hepatic Lipase (HL)
? Chylomicrons contain ApoB-48.
? VLDLs, IDLs and LDLs has ApoB-100.
HDL transfers
Apo E & Apo CII
to
Chylomicrons & VLDL
Different Lipoprotein Metabolism
Chylomicron
Metabolism
Metabolism of Chylomicrons
Surface Monolayer
Phospholipids
Free Cholesterol
Protein
Hydrophobic Core
Triglyceride
Cholesteryl Esters
Chylomicron Metabolism
Chylomicron Transport and Uptake
Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; , apolipoprotein C; E, apolipoprotein E;
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
? Assembled in intestinal mucosal
cel s
? Has lowest density
? It has largest size
? Highest % of lipids and lowest %
proteins
? Highest concentration of
Triacylglycerol (dietary origin)
? Chylomicrons carry dietary lipids
from intestine to Liver
? Responsible for physiological milky
appearance of plasma (up to 2
hours after meal)
? Chylomicron is a type of
Lipoprotein
? Formed in the intestinal
mucosal cells
? Due to aggregation of
dietary digested and
absorbed Lipids.
? The Chylomicrons has 99%
Lipids and 1% Proteins
? The predominant Lipid present
in Chylomicrons is
Triacylglycerol (TAG) of dietary
origin.
? The Apoprotein of Chylomicron is
B48
? Significant role of Chylomicron is
to transport dietary Lipids from
intestinal mucosal cell to Liver via
Lymph and Blood.
? Chylomicrons formed in
intestinal mucosal cells are
? First released in lymphatic
system
? Which then enters systemic
blood circulation via thoracic
duct.
? Chylomicrons in blood circulation are not
moved inertly
? But receives Apo C I and Apo E from the
circulating HDL and gets mature.
? Apo C I then stimulates the enzyme
Lipoprotein Lipase present in endothelial
lining of blood vessels of Adipose tissue
and Cardiac tissue.
? Activated Lipoprotein Lipase acts upon
TAG of Chylomicrons ,
? Hydrolyze it into free fatty acids and
Glycerol ,which then enters to
adjacent adiposecytes.
? Entered Free fatty acids TAG and
stored as reserve food material.
? The circulating Chylomicrons
are continuously acted upon by
Lipoprotein Lipase
? Most of the TAG is removed
from it and transformed to
Chylomicron remnant till they
reach Liver.
? The Liver has receptors for
Chylomicron remnant.
? Chylomicron remnant linked to
receptors of hepatocytes are
internalized and metabolized in
Liver.
? Chylomicrons transport dietary TAG
and Cholesterol from the intestine to
the peripheral tissues
? Lipoprotein lipase (LPL) is
activated by Apo C-II
? After most of the TG is removed,
Chylomicrons become
Chylomicron remnants. During
the process, CM give ApoC and
ApoA back to HDL
?CM remnants bind to specific
receptors on the surface of liver
cells through apo E and then the
complex is Endocytosed.
?Remnant receptor or ApoE
receptor or LRP (LDL receptor-
related protein)
? Chylomicron remnants deliver
dietary cholesterol and some
cellular cholesterol (via HDL)
to the liver.
? Half life of CM is short, less
than 1 hour.
Chylomicrons
Nascent Chylomicron are formed in the intestinal and
consists of rich in dietary TG + minimal amount of
dietary cholesterol + Apo (B-48)
Mature Chylomicron after Nascent chylomicron
passage to blood, addition of Apo C II and Apo E from
HDL
Lipoprotein lipase hydrolyzes TAG present in
Chylomicrons
Chylomicron remnant taken up by the liver through
endocytosis.
Apo C removed and returns back to HDL
Metabolism of VLDL and LDL
Formation and Fate Of VLDL
VLDL Metabolism
? The Lipoprotein Very Low
Density Lipoprotein (VLDL)
? Biosynthesized in
Hepatocytes and Intestinal
Mucosal Cells.
?The endogenously
biosynthesized Lipids are
aggregated
?Along with Apoprotein B-
100 to form VLDL.
? VLDL predominantly
contains Triacylglycerol of
endogenous origin.
Role Of VLDL
? VLDL facilitates in mobilizing out the
endogenously synthesized Lipids in
Hepatocytes and Intestinal mucosal cells.
? VLDL transports endogenous Lipids
from Liver to Extra Hepatocytes via
blood.
?Nascent VLDL accepts Apo
CII and Apo E from HDL
?This modify it to mature
VLDLs in blood.
? Nascent VLDL: contains Apo B-100
? Mature VLDL: Apo B-100 plus
Apo C-II and Apo E
(from HDL)
? Apo C-I is required for activation of
Lipoprotein lipase
? Lipoprotein lipase is required to
degrade VLDL TAG into Glycerol and
fatty acids
?Circulating VLDL on
action by Lipoprotein
Lipase hydrolyzes most
of its TAG.
?VLDL gets modified to
IDL and LDL.
? Thus intermediate product of
IDL and end product LDL are
formed from VLDL
? In blood circulation by action
of LPL on VLDL and removal of
TAG from it.
Normal VLDL Metabolism
Prevents the person
to
Suffer from Fatty Liver
? VLDL help in mobilizing out the
endogenously biosynthesized Lipids
of Hepatocytes.
? Normal Formation and mobilization
of VLDL prevents from accumulation
of excess Fat in the Liver and
develop Fatty Liver.
Modifications of Circulating VLDLs
VLDL IDL (returns Apo E to HDL) LDL
VLDL Metabolism
Dietary Carbohydrate Increases
VLDL Production
Plasma
Triglyceride
Dietary
(VLDL)
Carbohydrate
VLDL Remnants
IDL and LDL
? LDL results from loss of TAG in
VLDL
? LDL contains relatively more
Cholesterol esters
? LDL looses all Apo lipoproteins
except ApoB100.
Very Low Density Lipoprotein (VLDL)
Nascent VLDLare formed in the liver and consists of
endogenous TG + 17 % cholesterol + Apo (B-100)
Mature VLDL after Nascent VLDL passage to
blood, addition of ApoC II, ApoE and cholesterol
esters from HDL
Lipoprotein lipase (LPL) hydrolyzes TAG present
in VLDL
VLDL remnant containing less of TG and more of
cholesterol and taken up by the liver through
endocytosis.
Apo C removed and returns to HDL
LDL Metabolism
Most core lipid in LDL is Cholesterol ester.
ApoB100 is only Apolipoprotein in the surface.
Formation and Fate Of LDL
? Low Density Lipoprotein (LDL) is a
Lipoprotein formed from VLDL in
blood circulation.
? VLDL in blood circulation
receives Apo CII and Apo E from
the circulating HDL.
? Apo CI then stimulates the
Lipoprotein Lipase enzyme
present in the endothelial lining
of blood vessels.
? Lipoprotein Lipase then acts upon
TAG present in VLDL ,hydrolyze it
to Glycerol and free fatty acids
?LDL is the modified
form of VLDL formed
in blood circulation.
?LDL is remnant of
VLDL
?LDL is mostly associated
with Cholesterol and
Phospholipids with
minimal TAG
?Of endogenous origin
mobilized out from Liver.
? The major Apoproteins of LDL
is Apo B100
? Same as VLDL since LDL is
derived from VLDL
? Function of LDL is to transport
endogenously biosynthesized
Cholesterol from Liver to the
peripheral /extrahepatic tissues.
LDL Receptor
? Cell surface protein
? Recognizes Apolipoprotein B-100, present in VLDL,
IDL, LDL, and probably Apo-E
? LDL receptor is an integral membrane protein of
115 kDa,
? LDL receptor is highly regulated
? Intracellular cholesterol concentration increases,
the LDL receptor production is inhibited
LDL Receptor
?LDL receptor is also named
as ApoB100/ApoE
receptors
?Since ApoB-100 of LDL
binds to LDL receptor.
?The complexes of LDL and
receptor are taken into the
cells by endocytosis,
?Where LDL is degraded but
the receptors are recycled
? LDL receptors are found on cel
surface of many cel types of
extrahepatocytes.
? LDL is internalized by the tissues
when LDL get fixed to the LDL
receptors.
? LDL receptor mediates
delivery of Cholesterol
? By inducing endocytosis
and fusion with Lysosomes.
? Lysosomal lipases and
proteases degrade the LDL.
? Cholesterol then incorporates
into cell membranes or is
stored as cholesterol-esters of
extrahepatocytes.
LDL Receptor
LDL-Receptor-Related Protein-Associated
Protein (LRPAP1)
? Chaperone Protein which in humans is encoded
by LRPAP1 gene.
? Involved with trafficking of certain members of
LDL receptor family including LRP1 and LRP 2
? Acts to inhibit binding of all known ligands for
these receptors
? Prevent receptor aggregation and degradation in
endoplasmic reticulum, thereby acting as a
molecular chaperone.
Mutations and diseases related to
LRPAP1
? Abnormal ECM remodeling in neurons,
eye
?Dementia
?Myopia
?Marfans Syndrome
LDL Cholesterol levels
are
positively related to risk
of Cardiovascular
Disease.
?LDL values within
normal range is an
indication of healthy
status.
?But the high LDL levels
are abnormal .
? Cholesterol associated to this
high levels of LDL molecules
increases risk of
Atherosclerosis and CVD.
? Hence this LDL associated
Cholesterol is termed as "bad
Cholesterol"
Defect/Absence of
LDL Receptors
Leads to Accumulation of LDL
in Blood Circulation
Causing
Hypercholesteremia
and
Atherosclerosis
? Defect in LDL receptors on tissues
impairs LDL metabolism.
? Decreases LDL internalization
within the tissues.
? Increases abnormal levels of LDL in
blood (< 130 mg%).
? Increased LDL levels in
blood circulation due to
defect in LDL receptors is
termed as Type I a
Hyperlipoproteinemia.
? The major form of Lipid associated with LDL
is Cholesterol .
? Hence increased LDL levels is characterized
by Hypercholesterolemia.
? The Cholesterol associated with elevated
levels of LDL (more than its normal range) is
termed as bad Cholesterol,
? Since it increases the risk of Atherosclerosis
and its complications .
? Persons lacking the LDL
receptor suffer from Familial
Hypercholesteremia
? Due to result of a mutation in
a single autosomal gene
? Total plasma cholesterol and
LDL levels are elevated.
?Cholesterol Levels of:
?Healthy person = < 200 mg/dl
?Heterozygous individuals = 300 mg/dl
?Homozygous individuals = 680 mg/dl
High LDL levels can lead to
Cardiovascular Disease
Most Homozygous individuals
die of cardiovascular disease
in childhood
? LDL can be oxidized to form
oxidized LDL
? Oxidized LDL is taken up by
immune cells cal ed
macrophages.
? Macrophages become
engorged to form foam cells.
? Foam cel s become trapped in
the wal s of blood vessels and
contribute to the formation of
atherosclerotic plaques.
? Causes narrowing of the
arteries which can lead to
MI/heart attacks.
Familial hypercholesterolemia is due to a gene
defect in the LDL receptor
? Michael Palmer 2014
Role Of HDL
Reverse Transport Of
Cholesterol
? HDL is a high density
Lipoprotein.
? Nascent HDL is biosynthesized
in Liver.
? It is reservoir of Apoproteins
? HDL is the Lipoprotein, with highest
density.
? Since it is associated with 40-50% of
Apoproteins.
? The Apoproteins of HDL are Apo A I,
Apo A I , Apo C I,C I , Apo D and Apo E.
? HDL serves as a reservoir of
Apoprotein during its circulation.
? HDL gives it Apo CII and Apo E to
circulating nascent Chylomicrons
and VLDL .
? Nascent HDL of discoid shaped
(Empty Bag) biosynthesized in
Liver
? It is released in the blood
circulation for scavenging action.
The HDL has Scavenging Action
It serves as a
Scavenger For
Unwanted Body Lipids
? The Enzyme Lecithin Cholesterol Acyl
Transferase (LCAT) is associated with HDL
metabolism.
? Apo A I,A IV and CI stimulates the LCAT
activity of HDL.
? LCAT by its activity help in esterification of
free Cholesterol to Esterified
Cholesterol/Cholesterol Ester.
? HDL by its scavenging action collects the extra
non functional Cholesterol lying in blood
vessels and peripheral tissues.
? HDL esterifies Choleserol by its LCAT activity
and to HDL bag.
? The nascent HDL bags changes to spherical
shape .
? HDL is more associated with Phospholipids
and Cholesterol.
? The receptors for HDL are
present on Liver cells.
? HDL transports the excess,
unused Lipids from extra
hepatic tissues back to Liver for
its metabolism and excretion.
? The role of HDL is opposite to LDL.
? HDL transports Cholesterol From
extra hepatic tissues back to Liver.
? Thus the role of HDL is termed as
reverse transport of Cholesterol.
? Normal serum HDL levels are 30-60
mg%.
? The efficient activity of HDL is good
to the body
? As it prevents risk of Atherosclerosis
and their complications.
Reverse Cholesterol Transport (RCT)
High Density Lipoproteins (HDL ? Good)
? CETP by its activity modifies HDL 3
to HDL 2.
? HDL2 is then get internalized in
Hepatocytes for its final use.
? Cholesterol Ester carried by HDL to
hepatocytes is degraded to Bile
acids and Bile salts and get excreted
out.
Fate of HDL
HDL 2 binds SR-B1 receptor on Hepatocytes
And Other Cel s
Transfers Cholesterol &
Cholesterol ester to cell
Depleted HDL dissociates
& re-enters circulation
? HDL can bind to specific
hepatic receptors SR-B1
? But primary HDL clearance
occurs through uptake by
scavenger receptor SR-B1.
? SR-B1 can be upregulated in cells
when Cholesterol levels are low in
hepatic cells.
? SR-B1 is down regulated when
cholesterol levels are high in cells.
? Defect in low HDL synthesis in Liver
lowers the HDL activity and increases
the risk of Atherosclerosis.
? Defect in HDL receptors on Liver may
abnormally increase the HDL levels in
blood circulation and also increases the
risk of Atherosclerosis.
The Lecithin-Cholesterol Acyltransferase (LCAT)
reaction
Cholesterol esters can be stored inside lipoprotein
particles
HDL Interactions
with Other Particles
Tangier Disease: Disruption of Cholesterol
Transfer to HDL
? Michael Palmer 2014
HDL and Reverse Cholesterol Transport
Tangier Disease
LDL-R
LDL-R
50% of HDL C may
Return to the liver
On LDL via CETP
LDL/HDL Ratio and Cardiovascular Disease
? LDL/HDL ratios are used as a
diagnostic tool for signs of
Cardiovascular disease
? A good LDL/HDL ratio is 3.5
?LDL above normal range =
"Bad Cholesterol"
?HDL within normal range =
"Good Cholesterol"
-HDL above normal range =
"Bad Cholesterol"
? Protective role of HDL is not very
clear.
?An esterase that breaks down
oxidized lipids is associated with
HDL.
?It is possible (but not proven) that
this enzyme helps to destroy
oxidized LDL
Lipoproteins Facilitate Lipid
Transport
Effects Of Normal
Lipoprotein Metabolism
Normal LP Metabolism
? Maintains Normal levels of Lipoproteins
in the blood circulation by:
?Normal Formation of LP by specific tissues
?Normal Transformation and Transport of
LP in blood
?Normal Uptake of LP by specific tissues
? Normal Lipoprotein
Metabolism Reduces the risk
of:
?Atherosclerosis
?Myocardial Infarction
?Stroke
Lipoprotein Population Distributions
? Serum Lipoprotein
concentrations differ between
adult men and women.
? Primarily as a result of
differences in sex hormone
levels.
? Women having, on average, higher HDL
cholesterol levels and lower total
Cholesterol and TAG levels than men.
? The difference in total cholesterol,
however, disappears in post
menopause as Estrogen decreases and
use of Cholesterol is reduced.
PCSK9
Proprotein Convertase Subtilisin /Kexin type 9
PCSK9 - Mechanisms of Action
? PCSK9 is a Proprotein Convertase responsible for
? Degradation of low-density lipoprotein (LDL) receptors in
Liver.
? Mutations in PCSK9 gene cause familial
Hypercholesterolemia
? Due to reduced number of LDL receptors on surface of
hepatocytes.
? Decreases their ability to clear LDL cholesterol from plasma.
PCSK9 inhibitors ? Mechanisms of Action
? Conversely other PCSK9 mutations result in
? Unusually low concentrations of plasma LDL
cholesterol and a reduced risk of atherosclerotic
disease.
? Blocking activity of PCSK9 with monoclonal
antibodies reduces degradation of LDL receptors
? An injection of PCSK9-specific antibody
suppresses LDL-cholesterol concentrations.
? Increases clearance of LDL cholesterol
This post was last modified on 05 April 2022