overview of the lipid metabolism and drugs used for hyperlipidemia is presented

1. LIPID METABOLISM &
HYPOLIPIDAEMIC DRUGS
PRESENTED BY
S.SUCHARITHA
DEPARMAENT OF PHARMACOLOGY
SRI PADMAVATHI MAHILA VISWA VIDHYALAYA
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2. CONTENTS
 INTRODUCTION
 LIPIDS
 LIPOPROTEINS
 LIPOPROTEIN CLASSIFICATION
 LIPID METABOLISM
 EXOGENOUS PATHWAY
 ENDOGENOUS PATHWAY
 ATHEROGENESIS
 DRUG THERAPY
 SUMMARY
 REFERENCES
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3.  Cardiovascular and cerebrovascular ischemic diseases has becoming a
leading cause of morbidity and mortality
 A major cause for the development of IHD is high cholesterol & related
dyslipidemia
 Disorders of the metabolism of lipoproteins, including lipoprotein over
production and deficiency are classified as DYSLIPIDEMIA
 These may manifest in one or more of the following ways:
 Elevated total cholesterol levels
 Elevated LDL cholesterol levels
 Elevated triglycerides levels
 Decreased HDL cholesterol levels
INTRODUCTION
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4. LIPIDS
I)SIMPLE LIPIDS ( esters of fatty acids and alcohol)
1. Saturated fatty acids- which have sizeable effect of raising blood
cholesterol
Eg : lauric and palmitic acid
2. Mono unsaturated fatty acids- helps in lowering of LDL & VLDL
Eg :oleic acid & palmitoleic acid
3. Poly unsaturated fatty acids- they have hypolipidemic effect
Eg : linoleic acid & arachidonic acid
4. Trans fatty acids- they are harmful as they raises LDL & lowers
HDL
Eg : elaidic acid
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5. II)COMPOUND LIPIDS (also esters of fatty acids but have
other groups in their structure)
Eg: sulpholipids and phospholipids
III)NEUTRAL LIPIDS ( they are non polar lipids)
Eg: cholesterol, triglycerides, cholesteryl esters
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6. LIPOPROTEINS
 Lipids by definition are insoluble in water. In order to transport lipids such as
fatty acids, triacylglycerol, steroids and fat soluble vitamins in the blood
plasma, a carrier protein is required.
 The bulk of the body’s lipids (cholesterol, phospholipids and triacylglycerol),
are transported in the plasma by large complexes called lipoproteins. These
lipoproteins consist of a core of hydrophobic lipids surrounded by a shell of
phosphatidyl glycerol and proteins.
 The protein components of lipoproteins solubilise the hydrophobic lipids and
contain the cell targeting signals.
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7. GENERAL STRUCTURE OF
LIPOPROTEINS
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8. CLASSIFICATION OF LIPOPROTEINS
Lipoproteins can be classified in three ways-
1) Based on density-
They are separated by Ultracentrifugation. Depending upon the floatation
constant (Sf), Five major groups of lipoproteins have been identified that
are important physiologically and in clinical diagnosis.
(i) Chylomicrons, derived from intestinal absorption of triacylglycerol and
other lipids; Density is generally less than 0.95 while the mean diameter
lies between 100- 500 nm.
(ii) Very low density lipoproteins (VLDL), derived from the liver for the
export of triacylglycerol; density lies between 0.95- 1.006 and the mean
diameter lies between 30-80 nm.
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9. (iii) Intermediate density lipoproteins (IDL) are derived from the
catabolism of VLDL,with a density ranging intermediate between Very low
density and Low density lipoproteins i.e. ranging between 1.006-1.019 and
the mean diameter ranges between 25-50nm.
iv) Low-density lipoproteins (LDL), representing a final stage in the
catabolism of VLDL; density lies between 1.019-1.063 and mean
diameter lies between 18-28 nm
(iv) High-density lipoproteins (HDL), involved in cholesterol transport
and also in VLDL and chylomicron metabolism. Density ranges
between 1.063-1.121 and the mean diameter varies between 5-15
nm.
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10. Lipoproteins with high lipid content will have low density, larger size and
so float on centrifugation. Those with high protein content sediment
easily, have compact size and have a high density.
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11. 2) Based on electrophoretic mobilities
Lipoproteins may be separated according to their
electrophoretic properties into - α, pre β, β, and broad
beta lipoproteins.
 HDL are -α ,
 VLDL pre- β,
 LDL-β , and
 IDL are broad beta lipoproteins.
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12. 3)Based on nature of Apo- protein content
 Apoproteins are the transport proteins that bind to lipids to form
lipoproteins.
 Apo lipoproteins also serve as enzyme cofactors, receptor ligands,
and lipid transfer carriers that regulate the metabolism of lipoproteins
and their uptake in tissues.
 They have specific structural domains that are recognized by cell
receptors. All of the apoproteins have amphipathic α-helixes with the
hydrophobic side chains facing the lipid interior of the lipoprotein and
the hydrophilic residues interacting with the polar head groups of the
phospholipids or interacting with the aqueous solvent.
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13. FUNCTIONS OF APO PROTEINS
(1) They can form part of the structure of the lipoprotein, e.g.
Apo B, structural component of VLDL and Chylomicrons.
(2) They are enzyme cofactors, e.g. C-II for lipoprotein lipase, A-I
for lecithin cholesterol acyltransferase(LCAT), or enzyme
inhibitors, Eg: Apo A-II and Apo C-III for lipoprotein lipase,
Apo C-I for cholesteryl ester transfer protein.
(3) They act as ligands for interaction with lipoprotein receptors
in tissues, e.g. Apo B-100 and Apo E for the LDL receptor, Apo
A-I for the HDL receptor.
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14. Apo protein Lipoprotein classes Function
A-I Chylomicrons, HDL Activates LCAT
A-II Chylomicrons, HDL Inhibits LCAT, enhances hepatic lipase
activity.
A-IV Chylomicrons Unknown function
B-100 VLDL, IDL, HDL Necessary for binding to cell receptors,
LPLs.
B-48 Chylomicrons Necessary for binding to cell receptors,
LPLs.
C-I Chylomicrons, VLDL,
HDL
Cofactor for LCAT
C-II Chylomicrons, VLDL,
HDL
Activates LPL
C-III Chylomicrons,
VLDL,HDL
Regulates LPL
D HDL Essential for LCAT activity and
Cholesteryl ester transfer.
E ALL Binds to specific cell receptors.
CHARACTERISTIC DIFFERENCE OF LIPOPROTEINS
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16. LIPOPROTEIN METABOLISM
 Each class of lipoproteins has a specific role in lipid
transport and there are different pathways, which
are distinguished by the main Apoprotein (apo-B48,
apo-B100, apo-A1), respectively that are ligand for
key receptor, they are
LIPOPROTEIN
METABOLISM
EXOGENOUS
PATHWAY
ENDOGENOUS
PATHWAY
Apo-B100 Guided
pathway
a. Apo-A1 guided
pathway
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18. EXOGENOUS PATHWAY
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19. EXOGENOUS PATHWAY
 In intestine the triglycerides & cholesterol is incorporated into the core of
chylomicrons
 Chylomicrons are acted upon by the enzyme lipoprotein lipase .
 Reaction with lipoprotein lipase results in the loss of approximately 90% of
the triacylglycerol of chylomicrons and in the loss of Apo C (which returns to
HDL) but not Apo E, which is retained.
 The resulting chylomicron remnant is about half the diameter of the parent
chylomicron and is relatively enriched in cholesterol and cholesteryl esters
because of the loss of triacylglycerol
 Chylomicron remnants are taken up by the liver by receptor-mediated
endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed
and metabolized. for the synthesis of VLDL.

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21. In intestine the triglycerides & cholesterol is incorporated into
the core of chylomicrons
CMs are transported into circulation where apo-c is transferred to
it from HDL
In capillary endothelium Apo-C activates LPL which hydrolyses
CMs results in the loss of approximately 90% of the
triacylglycerol of chylomicrons and in the loss of apo C (which
returns to HDL)
After hydrolysis the result CMR which contain CE>TG gets
detached from capillary endothelium
Chylomicron remnants are taken up by the liver by receptor-
mediated endocytosis, and the cholesteryl esters and
triacylglycerols are hydrolyzed and cholesterol get liberated
EXOGENOUS PATHWAY

22. Uptake is mediated by apo E .
Hepatic lipase has a dual role: (1) it acts as a ligand to
facilitate remnant uptake and (2) it hydrolyzes remnant
triacylglycerol and phospholipids
Finally in this pathway
Fatty acids formed
from triglycerides are
delivered to fats and
muscles
Cholesterol serves as
a component for
synthesis of:
•Cell membrane
•Bile acids
•Steroids
•Also enters
endogenous pathway

23. ENDOGENOUS PATHWAY
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24. ENDOGENOUS PATHWAY
 The endogenous lipid transport system conveys lipid from liver to
peripheral tissues & back to the liver.
 It can be separated into two subsystems
 The atherogenic Apo-B100 lipoprotein governed
system(VLDL,IDL&LDL)
 The antiatherogenic Apo-A1 governed lipoprotein system(HDL)
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25. In liver the core lipids are packed together with Apo-B100 &
phospholipids into VLDL
Then these are secreted into plasma where Apo-CI,CII,CIII&E are
added to nascent VLDL from circulating HDL
The TGs in VLDL are hydrolysed by capillary LPL present on
luminal surface of blood vessel of various tissues forming FREE
FATTY ACIDS
VLDL after hydrolysis converted to VLDL remnants
If this VLDL further contains TGs then it is called as IDL
IDL further enters into liver through endocytosis via LDL
receptors which recogise Apo-E & hydrolyses the IDL to LDL with
help of HL
APO-B100 LIPOPROTEIN GOVERNED SYSTEM
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26. ENDOCYTOSIS OF LDL
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27. ENDOCYTOSIS OF LDL
1. LDLs bind to specific cell receptors located on the
plasma membrane of target cells.
2. The LDL receptor is a glycoprotein which contains a
domain with negatively charged residues.
3. This LDL binding domain has electrostatic interactions
with the positively charged arginine and lysine residues
of apo-B100.
4. The LDL receptors migrate to areas of the plasma
membrane specialized for endocytosis called coated
pits.
5. They are called coated pits because of the clathrin
protein coat on the cytoplasmic side of the membrane.

28. 6. Once the LDL binds to the receptor, the clathrin proteins
promote endocytosis.
7. Once the vesicle is inside of the cell, the clathrin
spontaneously dissociates from the endosomal vesicle.
8. The pH of the vesicle is lowered such that LDL
dissociates from the receptor.
9. The LDL receptors are recycled to the cell surface.
10. The vesicle fuses with a lysosome which then degrades
the lipoprotein to its primary components, fatty acids,
glycerol, cholesterol and amino acids. The cholesterol
is incorporated into the intracellular cholesterol pool
which is used for membrane or steroid synthesis.

29. HYPERCHOLESTEROLEMIA
 Familial hypercholesterolemia is a genetic disease caused by
a defective LDL receptor. There are five classes of mutations
that have been identified with the disease.
1. The receptor is not synthesized at all.
2. The receptor is not transported to the surface of the cell.
3. The receptor fails to bind LDL.
4. The receptor fails to cluster in the clathrin coated pits.
5. The receptor may fail to release LDL in the endosome.
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30.  Deficiency of the LDL receptor results in increased concentration of
LDL.
 Having one gene that produces an abnormal LDL receptor is called
heterozygous familial hypercholesterolemia
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31. APO-A1 CONTAINING LIPOPROTEIN SYSTEM
Nascent HDL is synthesised by intestine & liver which contain
mainly Apo-A1 & phospholipids
HDL3, generated from discoidal HDL by the action of LCAT,
accepts cholesterol from the tissues via the SR-B1 and the
cholesterol is then esterified by LCAT, increasing the size of the
particles to form the less dense HDL2.
HDL3 is then reformed, either after selective delivery of
cholesteryl ester to the liver via the SR-B1(REVERSE
TRANSPORT PATHWAY) or by hydrolysis of HDL2 phospholipids
and triacylglycerol by hepatic lipase. This interchange of HDL2
and HDL3 is called the HDL cycle.
Free apo A-I is released by these processes and forms pre -HDL
after associating with a minimum amount of phospholipids and
cholesterol
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32. A second important mechanism for reverse cholesterol transport
involves the ATP-binding cassette transporter A1 (ABCA1).
ABCA1 preferentially transfer cholesterol from cells to poorly
lipidated particles such as pre -HDL or Apo A-1, which are then
converted to HDL3 & then to HDL2 via discoidal HDL
These cholesterol rich HDL2 containing CE are exchanged for
triglycerides with VLDL,IDL,LDL & CMR with the help of CETP
The result is the cholesterol enrichment of Apo-B & triglycerides
enrichment of HDL2
TGs of HDL2
converts back to
HDL3 by
hydrolysis
HDL2 is
catabolised by
liver
HDL2 can return
to liver by SR-B1
receptors which
removes CH
converting it back
to HDL2
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33. FUNCTIONS OF HDL
 Scavenging action- HDL scavenges extra cholesterol from peripheral
tissues by reverse cholesterol transport
 HDL with the help of Apo E competes with LDL for binding sites on the
membranes and prevents internalization of LDL cholesterol in the smooth
cells of the arterial walls
 HDL contributes its Apo C and E to nascent VLDL and chylomicrons for
receptor mediated endocytosis
 HDL stimulated prostacyclin synthesis by the endothelial cells, which
prevent thrombus formation
 HDL also helps in the removal of macrophages from the arterial walls .
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34. ATHEROGENESIS
 Atheroma is a focal disease of the intima of large and medium-sized
arteries.
 Lesions evolve over decades, during most of which time they are
clinically silent, the occurrence of symptoms signalling advanced
disease.
 Presymptomatic lesions are often difficult to detect non-invasively,
although ultrasound is useful in relatively static and superficial
arteries (e.g. the carotids), and associated changes such as reduced
aortic compliance and arterial calcium deposition can be detected by
measuring, respectively, aortic pulse wave velocity and coronary
artery calcification.
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35. ATHEROGENESIS
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36. ATHEROGENESIS
endothelial dysfunction, altered PGI2, NO biosynthesis
Injury of endothelium, expression of adhesion molecules, migration
of monocytes
transport of LDL particles to blood vessels,
generation of free radicals by endothelium that oxidizes LDL
results in lipid peroxidation
oxLDL taken up by macrophages via SR-B1 receptors forming
FOAM CELLS that releases pro inflammatory cytokines
FATTY STREAK
Cholesterol mobilised from artery wall & transported to plasma in
the form of HDL
Activated platelets, macrophages & endothelial cells cause
proliferation of smooth muscle and results in ATHEROMATOUS
PLAQUE
PLAQUE RUPTURE ,THROMBOSIS ,STABILISATION OF
PLAQUE
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37. ATHEROGENESIS
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38. DRUG THERAPY IN ATHEROGENESIS
CLASSIFICATION
1 . HMG-CoA reductase inhibitors (Statins):
Lovastatin Simvastatin
Pravastatin Atorvastatin
Rosuvastatin Pitvastatin
2. Bile acid sequestrants (Resins):
Cholestyramine Colestipol
3. Activate lipoprotein lipase (Fibric acid derivatives):
Clofibrate Gemfibrozil
Bezafibrate Fenofibrate
4. Inhibit lipolysis and triglyceride synthesis:
Nicotinic acid
5.Antioxidant:
Probucol
6. Sterol absorbtion inhibitors:
Ezetimibe
7.Others:
Gugulipid.
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39. HMG CO-A REDUCTASE INHIBITORS OR
STATINS
DRUGS
 Lovastatin Rosuvastatin
 Atorvastatin Pitvastatin
 Simvastatin Pravastatin
ADVERSE EFFECTS
 Gastro intestinal disturbance
 Muscle pain, Headache, Insomnia
 Rashes, Rarely myopathy & angio-oedema
USES
 First time of drug both familial & secondary
hyperlipidemia as in DIABETES
MILLETUS.
 Useful in lowering morbidity & mortality in
patients with coronary heart disease
HMG CO-A
MEVALONIC
ACID
CHOLESTROL
STATINS
HMG CO A
REDUCTASE
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40. FIBRATES/ FIBRIC ACID DERIVATIVES
DRUGS
 Clofibrate Gemfibrozil
 Bezafibrate Fenofibrate
OTHER ACTIONS
 They also increases HDL
 They also increases oxidation of fatty acids in liver
& decreases lipolysis in adipose tissue
ADVERSE EFFECTS
 GI disturbances
 Skin rashes, Headache, Myositis
 Muscle cramps, Blurred vision
 Rhabdomyolysis
FIBRATES
LPL SYNTHESIS
Degradation of VLDL
TGs
LDL
Activates PPAR α
receptors
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41. BILE ACID BINDING RESINS
DRUGS
 Cholestyramine
 Colestipol
USES
 Used in patients with raised LDL
levels
 Used along with lovastatin or
nicotinic acid
BAB RESINS
(+vely charged)
Bind to –vely charged
bile acids in intestine
Prevent absorption of
cholesterol
Fall in plasma
cholesterol
LDL
levels
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42. INHIBITORS OF LIPOPROTEIN & TRIGLYCERIDES
SYNTHESIS
DRUGS
 Nicotinic acid
ADVERSE EFFECTS
 Cutaneous vasodilatation
 Feeling of warmth mediated by PGs
 Dyspepsia, Dryness & Pigmentation
USES
 Used in hypertriglyceridemia with low
HDL level
Nicotinic acid
Inhibit TG synthesis
in the liver HDL
Production of
VLDL
LDL
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43. STEROID ABSORPTION INHIBITORS
Adverse effects
 diarrhoea,
 abdominal pain or headache
 rash and angio-oedema
USES
 As an addition to a statin when response
has been inadequate (ezetimibe).
 For hypercholesterolemia when a statin is
contraindicated.
 Uses unrelated to atherogenesis, including:
 Pruritis in patients with partial biliary
obstruction (bile acid-binding protein)
 Bile acid diarrhoea.
Ezetimibe & its
metabolites
Concentrated in the brush
border of the small intestine
Inhibit a specific transport
protein NPC1L1
Cholesterol absorption
LDL
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44.  Antioxidant
 Probucol decreases LDL & increases HDL
 It is generally not preferred
o Miscellaneous
 Gugulipid decreases the plasma cholesterol & TGs
 Omega 3 Fatty Acids (Fish Oils)-The most widely used n-3 PUFAs for
the treatment of hyperlipidemia are the two active molecules in fish oil:
Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA).
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45. INVESTIGATIONAL
Investigational classes of hypolipidemic agents:
 CETP inhibitors (cholesteryl ester transfer protein), 1
candidate is in trials. It is expected that these drugs will mainly
increase HDL while lowering LDL;
 Squalene synthase inhibitor;
 ApoA-1 Milano
 Succinobucol (AGI-1067), a novel antioxidant, failed a phase
3 trial
 Apo protein-B inhibitor Mipomersen (approved by the FDA in
2013 homozygous familial hypercholesterolemia).
 PCSK9 Monoclonal antibody inhibitors
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46. SUMMARY
 Lipid s are fats that are either absorbed from food or synthesized by the liver.
 Lipids are transported by a special protein called lipoprotein & gets metabolised
by 2 major pathways i.e., exogenous & endogenous pathway
 Any alteration in the lipid metabolism will leads to the one of the following
disorder
 Hyper cholesterolemia
 Hyper triglyceridemia
 Chylomicron retention disease
LIPIDS
EXOGENOUS
ENDOGENOUS
VLDL
IDL
LDL
HDL
store energy in
adipocytes &
muscle cells
cell membranes,
steroids, bile acids
and signalling
molecules.
LIPOPROTEI
N
ATHEROSCELEROSIS
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47. REFERENCES
 RANG AND DALES PHARMACOLOGY: 8TH ADDITION.
 PRINCIPLES OF PHARMACOLOGY BY H.L.SHARMA &
K.K.SHARMA
 ESSENTIALS OF MEDICAL PHARMACALOGY BY K.D.TRIPATI 6TH
EDITION
 A CASE ORIENTED APPROACH TOWARDS BIOCHEMISTRY
BY: NAMRATA CHHABRA, SAHIL CHHABRA
 REVIEW OF LIPOPROTEINS BY BRYANT MILES
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