LIPID METABOLISM &HYPOLIPIDAEMIC DRUGS

PRESENTED BY S.SUCHARITHA DEPARMAENT OF PHARMACOLOGY SRI PADMAVATHI MAHILA VISWA VIDHYALAYA

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CONTENTS INTRODUCTION LIPIDS LIPOPROTEINS LIPOPROTEIN CLASSIFICATION LIPID METABOLISM EXOGENOUS PATHWAY ENDOGENOUS PATHWAY ATHEROGENESIS DRUG THERAPY SUMMARY REFERENCES

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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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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 acid2. Mono unsaturated fatty acids- helps in lowering of LDL &

VLDL Eg :oleic acid & palmitoleic acid3. Poly unsaturated fatty acids- they have hypolipidemic effect Eg : linoleic acid & arachidonic acid4. Trans fatty acids- they are harmful as they raises LDL & lowers

HDL Eg : elaidic acid

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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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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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GENERAL STRUCTURE OF LIPOPROTEINS

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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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(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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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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2) Based on electrophoretic mobilitiesLipoproteins 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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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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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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Apo protein Lipoprotein classes FunctionA-I Chylomicrons, HDL Activates LCATA-II Chylomicrons, HDL Inhibits LCAT, enhances hepatic

lipase activity.A-IV Chylomicrons Unknown functionB-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,

HDLCofactor 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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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 areLIPOPROTEIN

METABOLISM

EXOGENOUS PATHWAY

ENDOGENOUS PATHWAY

Apo-B100 Guided pathway

a. Apo-A1 guided pathway

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EXOGENOUS PATHWAY

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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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

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

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ENDOGENOUS PATHWAY

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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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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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ENDOCYTOSIS OF LDL

ENDOCYTOSIS OF LDL1. 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.

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.

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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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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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APO-A1 CONTAINING LIPOPROTEIN SYSTEMNascent 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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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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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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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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ATHEROGENESIS

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ATHEROGENESISendothelial 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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ATHEROGENESIS

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DRUG THERAPY IN ATHEROGENESISCLASSIFICATION1 . HMG-CoA reductase inhibitors (Statins): Lovastatin Simvastatin Pravastatin Atorvastatin Rosuvastatin Pitvastatin2. Bile acid sequestrants (Resins): Cholestyramine Colestipol 3. Activate lipoprotein lipase (Fibric acid derivatives): Clofibrate Gemfibrozil Bezafibrate Fenofibrate4. Inhibit lipolysis and triglyceride synthesis: Nicotinic acid5.Antioxidant: Probucol6. Sterol absorbtion inhibitors: Ezetimibe 7.Others: Gugulipid.

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HMG CO-A REDUCTASE INHIBITORS OR STATINSDRUGS Lovastatin Rosuvastatin Atorvastatin Pitvastatin Simvastatin PravastatinADVERSE EFFECTS Gastro intestinal disturbance Muscle pain, Headache, Insomnia Rashes, Rarely myopathy & angio-oedemaUSES 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

STATINSHMG CO A

REDUCTASE

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FIBRATES/ FIBRIC ACID DERIVATIVES

DRUGS Clofibrate Gemfibrozil Bezafibrate FenofibrateOTHER ACTIONS They also increases HDL They also increases oxidation of fatty acids in liver

& decreases lipolysis in adipose tissueADVERSE 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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BILE ACID BINDING RESINS

DRUGS Cholestyramine ColestipolUSES 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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INHIBITORS OF LIPOPROTEIN & TRIGLYCERIDES SYNTHESIS

DRUGS Nicotinic acidADVERSE EFFECTS Cutaneous vasodilatation Feeling of warmth mediated by PGs Dyspepsia, Dryness & PigmentationUSES Used in hypertriglyceridemia with low

HDL level

Nicotinic acid

Inhibit TG synthesis in the

liverHDL

Production of VLDL

LDL

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STEROID ABSORPTION INHIBITORSAdverse effects diarrhoea, abdominal pain or headache rash and angio-oedemaUSES 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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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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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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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

LIPIDSEXOGENOUS

ENDOGENOUS

VLDLIDLLDLHDL

store energy in adipocytes & muscle cells

cell membranes, steroids, bile acids and signalling molecules.

LIPOPROTEIN

ATHEROSCELEROSIS

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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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