3 Literature Review

Chapter 3 Review of literature

CHAPTER-3

REVIEW OF LITERATURE

3.1 Hyperlipidemia

Hyperlipidemia refers to elevated levels of lipids and cholesterol in the blood

and is also identified as dyslipidemia to describe the manifestations of different

disorders of lipoprotein metabolism. Alteration and/or abnormality in the metabolism of

lipid and lipoproteins is a very common condition that taken place within general

population and it consider as one of the main risk factor in the incidence of

cardiovascular disease due to their influence on atherosclerosis.11

Critical Factors that Play Role in Hyperlipidemia Incidence

There are several factors which play significant role in the incidence of this

medical problem like family history, Chronic diseases (diabetes mellitus, renal failure,

nephritic syndrome and hypothyroidism), alcoholism and smoking, obesity and

unhealthy diets intake.12

3.1.1 Classifications of Hyperlipidemia

Besides the above classifications i.e., primary and secondary hyperlipidemia

subtypes, hyperlipidemia also classified according to the type of lipid elevated which is

hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia.

Table-3.1 Based on therapeutic considerations, Hperlipidaemias may be classified13

Category Increased lipoprotein Increased Serum lipid

Hypercholesterolemia LDL Cholesterol

Mixed hyperlipidemia LDL+VLDL Cholesterol+Triglycerides

Hypertriglyceridemia VLDL Triglycerides

Department of Pharmacolgy Page 7


Hyperlipidaemias may be primary or secondary in aetiology.

Table-3.2 Classification of Primary Hyperlipidaemias14

Type

Average of

overnight serum

Elevated particles

Associated clinical disordersSerum

TCSerum

TG

ICreamy top layer

ChylomicronsLipoprotein lipase deficiency, apolipoprotein C-II deficiency

N ++

IIa Clear LDL

Familial hypercholesterolemia, polygenic hypercholesterolemia,

nephrosis, hypothyroidism, familial combined hyperlipidemia

++ N

IIb Clear LDL, VLDL Familial combined hyperlipidemia ++ +

III Turbid IDL Dysbetalipoproteinemia + +

IV Turbid VLDL

Familial hypertriglyceridemia, familial combined hyperlipidemia,

sporadic hypertriglyceridemia, diabetes

N+ ++

VCreamy

top, turbid bottom

Chylomicrons, VLDL

Diabetes + ++

3.1.2 Causes of Secondary hyperlipidemia

Anabolic steroid use



Diabetes Glycogen storage diseases

Hypothyroidism Liver disease, obstructive

Medications: corticosteroids, bile acid-binding resins, anticonvulsants,

Certain oral contraceptives, Accutane® (isotretinoin), Depo-provera®

Overweight or obesity

Renal diseases

Therapeutic diet: ketogenic; high carbohydrate

3.2 Lipids

Lipids are a heterogeneous group of compounds, including fats, oils, steroids,

wax and related compounds, which are related more by their physical than by

their chemical properties. Lipids may be regarded as organic substances

relatively insoluble in water, soluble in organic solvents (alcohol, ether etc.)

3.2.1 CLASSIFICATION:16

Lipids are broadly classified into simple, complex and derived, which are

further subdivided into different groups.

1. Simple lipid

2. Compound/complex lipid

Fig-3.1 Classification of lipids

Table 3.3 Etiologies of Hyperlipidemias15



Phenotype

Elevated

Particles

Major Lipid

Abnormality Frequency Etiology

IChylomicron

TG Very rare

LPLdeficiency, apoC-

II deficiency LPL eg,

systemic

lupuserythematosus

IIA LDL LDL-C Common

FH, FCH,

polygenic

hypercholesterimia

,hypothyroidism,

IB LDL and

VLDLLDL-C, TG Common Similar to type IIA

HLP

III IDL TC, TG Rare

ApoE-2

homozygosity (E-

2/E-2) plus obesity,

diabetes mellitus,

renal disease,

hypothyroidism, or

IV VLDL TG Common

FCH,FH,metabolien

docrine disease,

renal disease, liver

disease, ethanol

use/abuse,

V

Chylomicron

and VLDL TGUncommon

Usually resultsfrom a

combination of any

twoconditions that

cause type IV HLP

1.Simple lipids: These are esters of fattyacids with various alcohols.



(a) fats and oils: Esters of fatty acids with glycerol. The difference between fat

and oil is only physical. Thus, oil is a liquid while fat is a solid at room

temperature.

(b) waxes: Esters of fatty acids(usually long chain)with alcohols other than

glycerol. these alcohols may be aliphatic or alicyclic.

2. Compound/Complex lipid: Esters of fatty acids containing groups in addition to

an alcohol

(a) Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a

phosphoric acid residue.They frequently have nitrogen containing bases and

other substituents.

b) Glycolipids: Lipids containing a fatty acid, sphingosine, carbohydrate and

nitrogenous base. glycerol and phosphate are absent e.g.cerebrosides,

(c)lipoproteins: macromolecular complexes of lipids with protein.

(d) Other complex lipids : Lipids such as sulfolipids, and amino lipids.

3.precursor and derived lipids: these include fatty acids,glycerol, steroids, other

alcohols, fatty aldehydes and ketone bodies, hydrocarbones, lipid-soluble vitamins and

hormones.

Major lipids found in the blood stream are.16

1. Triglycerides

2. Phospholipids

3. Cholesterol

4. Free fatty acid

3.2.2 Triglycerides17

Triglycerides also know as triacylglycerol or triacylglycerides are glycerides

in which the glycerol is esterified with three fatty acids. They are the main

constituents of vegetable oil and animal fats. They play an important role in the

metabolism as energy source. They contain a bit more than twice as much as energy

9k.cal/gm as carbohydrates and proteins. Triglycerides are water insoluble, non-polar

neutral fats. These fats primarily occur in adipocytes of adipose tissue

predominantly found in the subcutaneous layer and in the abdominal cavity, having

specialized storage of TGs.The fat is stored in the form of globules dispersed in



the entire cytoplasm. TG synthesis mostly occurs in liver and adipose tissue.

Table-3.4 Classification of Triglycerides18

Fig 3.2 Synthesis of Triglycerides

3.2.3 Cholesterol

Cholesterol is a steroidal alcohol found exclusively in animals and present in

virtually all cells and body fluids. It is a precursor of numerous physiologically

important steroids like bile acids. About two thirds of cholesterol is esterified with

fattyacids to form cholesterol esters.

Cholesterol is essential for:

1. Formation and maintenance of cell membranes helps the cells to resist changes

in temperature and protects and insulates nerve fibers.

2. Formation of sex harmones, testosterone, progesterone, estradiol.

3. Production of bile acids.

4. Conversion into vitamin D in the skin when exposed to

sunlight. Cholesterol literally means “solid alcohol from bile”.Cholesterol and

triglycerides are two forms of lipid/fat. Cholesterol is made primarily in the liver


<150mg/dl Normal Triglycerides

150-199mg/dl Borderline Triglycerdies

200-499mg/dl High triglycerides

<500mg/dl Very high triglycerides


(about 1,000 mg per day), but it is also created by cells lining the small intestine

and by the individual cells in the body. Cholesterol and other fats cannot dissolve in

blood. They have to be transported to and from the cells by special carriers called

“lipoproteins”. Important lipoproteins are LDL and HDL.19

The enzymes involved in the cholesterol synthesis are found in the cytosol

and microsomal fractions of the cell. Acetate to acetyl Co A provides all the carbon

atoms in the cholesterol. Cholesterol synthesis takes place in 5 stages, which

includes synthesis of HMG CO A, formation of mevalonate (6c), production of

isoprenoid units (5c), synthesis of squalene (30c) and conversion of squalene to

cholesterol (27c).

Cholesterol biosynthesis is controlled by the rate-limiting enzyme HMG

CoA reductase, at the beginning of the pathway, which is found in association with

endoplasmic reticulum and subjected to different metabolic controls like feed back control,

hormonal regulation, inhibition by drugs and inhibition by bile acids.

Table -3.5 Desirable levels of cholesterol

3.2.4 FATTY ACIDS

These are straight-chain carbon compounds of varying lengths. They

may be saturated, containing no double bonds, monounsaturated, with one

double bond, or polyunsaturated, with more than one double bond Fatty

acids can esterify with glycerol to form triglycerides or be non-esterified

(NEFAs) or free. Plasma NEFAs liberated from adipose tissue by lipase

activity are transported to the liver and muscle mainly bound to albumin. The

NEFAs provide a significant proportion of the energy requirements of the

body.20

The fatty acids in the body are mostly oxidized by beta-oxidation which

takes place in 3 stages i.e. activation of fatty acids occurring in the cytosol, transport

of FAs into mitochondria and beta-oxidation in the mitochondrial matrix.


<200 Desirable

200-239 Boderline high

>240 High


The dietary carbohydrates and amino acids, when consumed in excess

are converted to FAs and stored as TGs. It occurs predominantly in liver, kidney,

adipose tissue and lactating mammary glands. The enzymes required for fatty acid

synthesis are present in the cytosomal fraction of the cell. Acetyl CoA is the

source of carbon atoms, NADPH provides the reducing equivalent and ATP

supplies energy for fatty acid formation. The synthesis occurs in 3-stages

including production of acetyl CoA and NADPH, conversion of acetyl CoA to

malonyl CoA, reactions of FA synthase complex.

Fig-3.3 Synthesis of cholesterol

3.2.5 PHOSPHOLIPIDS:

Phospholipids are triglycerides that are covalently bonded to a phosphate group

by an ester linkage. The diglyceride is composed of a glycerol backbone that has

esterified to two fattyacids.The hydrocarbon chains are hydrophobic (FAs), the

charges on the phosphate and group make that portion of molecule hydropyllic.The

result is an amphophilic molecule.There are two classes of phospholipids, which

include sphingomyelins where sphingosine as the alcohol and

glycerphospholipids/phosphoglycerides. glycerol is the alcohol.



Phospholipids perform important functions including regulating membrane

permeability and in maintaining electron transport chain in mitochondria. Due to

their amphophilic nature, they can combine with polar and non-polar compounds in

the cell. They serve as a precursor for synthesis of eicosanoids, participate in the

reverse cholesterol transport and thus help in the removal of cholesterol from the

body.

They are synthesized from phosphatidic acid and 1, 2-diacyl glycerol, which

are also intermediates in the production of triglycerides. Phospholipid synthesis,

occurs in the endoplasmic reticulum. Lecithin, cephalin, phosphotidyl serine,

phosphotidylinostol, phosphotidylglycerol, are important phospholipids. Phospholipids

are degraded by phospholipases, which cleave the phosphodiester bonds. E.g.:

Phospholipase A1, A3, phospholipase C and phospholipase .

Fig-3.4 Synthesis of phospholipids



3.3 LIPPROTEINS

Lipoproteins are the “packages” in which cholesterol and triglycerides (lipids)

are transport through out the body by combining with proteins. Lipoproteins

contain cholesterol, phospholipids and triglycerides at the core and an outer layer of

protein called “apolipoproteins/apoproteins”. The lipid constituents are water

insoluble and apoproteins are water soluble.21

Dependining upon their lipid carrying capacity Lipoproteins are classified

into clases

1. Chylomicrons

2. LDL (Low-density lipoproteins)

3. VLDL (very low-density lipoproteins)



4. IDL (Intermediate density lipoproteins)

5. HDL (High-density lipoprotein)

Fig-3.5 Structure of lipoprotein

3.3.1. CHYLOMICRONS (CMs):These are the largest plasma proteins and the only lipoproteins that float to

the top of the plasma tube. The formation of chylomicrons takes place in the

intestine during solubilization of dietary fats by bile acids. CMs are metabolized in the

liver resulting in the formation of VLDL which in turn is catabolised to form IDL,

which is further catabolised to LDL.

CMs VLDL IDL LDL

CMs enter into blood stream via. Lymphatic system, where they acquire apo

c-II and apoE from plasma HDL. The apoC II in CMs activates LPL in the

presence of phospholipids. This LPL removes fatty acids of CMs from triglycerides.

A progressive decrease in particle diameter occurs as triglycerides in the core are

depleted and small apoproteins are transported to HDL. The resultant CM remnants

are taken up by receptor-mediated endocytosis, as into hepatocytes. The

concentration of CMs can be controlled only by reducing dietary fat consumption.

There is no current therapeutic approach that will enhance CM catabolism except

for insulin replacement in patients with type–I diabetis. CMs function to deliver

dietary TGs to adipose tissue and muscle and dietary cholesterol

to liver.



Fig-3.6 Chylomcron structure

3.3.2. VERY LOW DENSITY LIPOPROTEINS (VLDLs):VLDLs are the next in size to CMs, which are responsible to carry

endogenous TGs from the liver into the blood stream to other parts. They contain

TGs, cholesterol esters, phospholipids and apoproteins. Like nascent CMs, newly

released VLDL acquires apo C and apo E from circulating HDLs.

Lipoprotein lipase (LPL) located on capillary endothelial cell surface

catalyses the release of fatty acids portion of VLDL to adipose tissue and muscle in

the same way as CMs. The action of LPL converts VLDL to intermediate density

lipoproteins (IDLs), also termed as VLDL remnants. The further losses of TGs in

IDLs by hepatic glyceride hydrolase lipase results in the generation of LDL. The

apo Cs are converted to HDLs.

Apo E plays an important role in the metabolism of TG rich

lipoproteins CMs, CM remnants, VLDL and IDL and has number of functions

related to the binding and uptake of plasma proteins. In transgenic mice, over

expression of apo E by macrophages inhibits hypercholesterolemia-induced

atherosclerosis.22

Fig-3.7 Very low density lipoprotein



3.3.3. INTERMEDIATE DENSITY LIPOPROTEINS (IDLs):

Intermidiate density lipoproteins comes next in the catabolic transformation

of VLDL to LDL. IDLs are formed from VLDLs with the removal of TGs.

The fate of IDLs is either conversion to LDLs or direct uptake by the

liver. Conversion of IDLs to LDLs occur as more TGs are removed .The liver take up

IDLs after they have interacted with the LDL receptor to form a complex, which is

endocytosed by the cell. For LDL receptors to recognize IDLs requires the presence

of both apo B-100 and apo E (the LDL receptor is also called the apo B-100/apo E

receptor). Apo E is important in cholesterol uptake by LDL receptors.

3.3.4. LOW DENSITY LIPOPROTEINS (LDLs):

Low density lipoproteins arise from VLDLs by the action of lipoprotein lipase.

The cellular requirement for cholesterol as a membrane component is satisfied by

CMs and LDLs. LDLs is the primary plasma carriers of cholesterol for delivery to all

tissues .It contain 60-70% total cholesterol.

The apoprotein of LDL is apoB-100.LDLs is taken up by cells via. LDL

receptor- mediated endocytosis, as described above for IDL uptake. The uptake of

LDLs occurs predominantly in liver 75%,adrenals and adipose tissue. As with IDLs,

the interaction of LDL with LDL-receptors requires the presence of apo B-100.The

endocytosed membrane vesicles endosomes fuse with lysosomes, in which the

apoprotein are degraded and the cholesterol esters hydrolyzed to yield free



cholesterol. The cholesterol is then incorporated into the plasma membranes as

necessary. Excess intracellular cholesterol is re-esterified by acyl -Co A-cholesterol

acyl transferase ACAT, for intracellular storage.23

Insulin and Tri-iodothyronine( T3) increases the binding of LDL to liver

cells, where as glucocorticoids has opposite effect. The precise mechanism for this

effect in not clear but may be mediated through the regulation of apoB degradation.

The effects of insulin and T3 on hepatic LDL binding may explain the

hypercholesterolemia and increased risk of atherosclerosis that have been shown to

be associated with uncontrolled diabetes or hypothyroidism.

An abnormal form of LDL, identified as “lipoprotein-x Lp-x” predominates in

the circulation of patients suffering cholestatic liver disease. In this case,there is an

elevation in the level of circulating free cholesterol and phospholipids. LDL often

called as “bad” cholesterol because LDL easily adheres to the wall of arteries, which

leads to initiation of atherogenic process.24

3.3.5 High density lipoproteins(HDL-C)

High density lipoprotein is the smallest lipoprotein. It contains 20-30% of

person’s total cholesterol. HDL is often called “good cholesterol” which finds and

removes, stuck LDL at the apo B and E receptors of peripheral cells and brings them

back to the liver, where they get discarded. HDLs are synthesized in the liver and

small intestine, as primarily protein rich disc shaped particles. The newly formed

HDLs are devoid of any cholesterol and cholesterol esters.

The primary apoproteins of HDL are apoA-1, apoC-1, apoC-11and apo E.

Infact, the major function of HDL is to act as circulating stores of apoC-1, apoC-11

and apoE. HDLs are converted into spherical lipoproteins particles through

accumulation of cholesterylesters. The accumulation converts HDLs to HDL2 and

HDL3. Any free cholesterol present in CM remnant and VLDLremnants can be

esterified through the action of Lecithin cholesterol acyl transferase(LCAT). LCAT is

synthesized in liver and so named because it transfers a fattyacid from the C-2

position of lecithin to the C-3OH of cholesterol, generating a cholesteryl ester and

lysolecithin. The activity of LCAT requires interaction with apoA-1, which is found on

the surface of HDLs.25

Cholesterol rich HDLs return to liver, where they are endocytosed. Hepatic



uptake of HDLs or reverse cholesterol transport may be mediated through an HDL-

specific apoA1receptor or through lipid-lipid interactions.HDLs also get cholesterol

from macrophages by the same way. HDLs also acquire cholesterol by extracting it

from cell surface membranes,which lead to lowering of intracellular cholesterol,

since the cholesterol stored within cells as cholesteryl esters will be mobilized to

replace the cholesterol removed from the plasma membrane.

The cholesterol esters of HDLs can also be transferred to VLDLs and

LDLs through the action of HDL-associated enzyme, cholesterol ester transfer

protein CETP. This has the added effect of allowing the excess cellular cholesterol to

be returned to the liver through the LDL-receptor pathway as well as the HDL-receptor

pathway.

3.3.6 [LP (a)]-

[Lp(a)] consists of an LDL-like particle and the specific apolipoprotein(a)

[apo(a)], which is covalently bound to the apoB of the LDL like particle. Lp(a)

accumulates in the vessel wall and inhibits binding of Plasminogen (PLG) to

the cell surface, reducing plasmin generation which increases clotting. This

inhibition of PLG by Lp(a) also promotes proliferation of smooth muscle cells

causing generation of clots and atherosclerosis.

Fig-3.8 Transport of lipoproteins



Lipoprotein particles are produced by hepatocytes (liver cells) and enterocytes from

TAG, cholesterol, apolipoproteins, and phospholipids. The hydrophobic TAG and

cholesteryl esters make up the central part, whilst apolipoprotein strands, cholesterol

molecules and phospholipids are located in the outer shells.

Although LDL cholesterol (LDL-C) is associated with an increased risk of coronary

heart disease, other lipoproteins and their constituents, apolipoproteins, may play an

important role in atherosclerosis. Elevated levels of apolipoprotein (apo) B, a

constituent of atherogenic lipoproteins, and reduced levels of apo A-I, a component of

anti-atherogenic HDL, are associated with increased cardiac events. Apo B, apo A-I and

the apo B/apo A-I ratio have been reported as better predictors of cardiovascular events

than LDL-C and they even retain their predictive power in patients receiving lipid-

modifying therapy. Measurement of these apolipoproteins could improve

cardiovascular risk prediction.

Apolipoproteins are protein components found on the outside of the lipoprotein,

which emulsify the lipoprotein particle to make it more stable in aqueous solution for

carriage in plasma. They also interact with cellular receptors that determine how and

where lipoprotein particles are metabolised. Each lipoprotein particle has a specific set

of apolipoproteins. Apolipoproteins are important because they control lipoprotein

metabolism. Apolipoprotein and LDL receptor genes have been identified, sequenced

and mapped to chromosomes. Apolipoprotein disorders are known to lead to defects of

lipid metabolism

The important apolipoproteins are:

ApoA - present in HDLs. The binding of ApoA-I to cellular receptors

mediates the efflux of cholesterol from peripheral cells, and the influx of

cholesterol into hepatocytes.

ApoB - encourages cellular uptake of LDL. ApoB-100 is derived from liver

and forms part of LDL. ApoB-48 is derived from the gut and is found in

chylomicrons.

ApoC - synthesised in the liver and is a peripheral activator of lipoprotein

lipase (LPL). It is transferred between lipoproteins

ApoE - stabilises VLDL for cellular uptake.

Apo(a) - links with aAoB-100 to oxidise LDL, giving Lp(a) lipoprotein

particles.



Table- 3.6 Characteristics of plasma lipoproteins26

Lipoprote

in

class

Major lipid

constituent

Diameter

(nm)

Site of

synthesis

Mechanism(s)

of

catabolism

Chylomicrons

and remnants

Dietary TGs and

cholesterol

100-1000 Intestine TG hydrolysis by LPL

ApoE-mediated

remnant uptake by liver

VLDL Endogenous or

hepatic TGs

30–80 Liver TG hydrolysis by LPL

IDL Cholesteryl

esters and

"endogenous"

TGs

25–50 Product of

VLDL

Catabolism

50% converted to

LDL mediated by

HDL, 50% apoE-

mediated uptake by

liverLDL Cholesteryl esters 18–28 Product of

VLDL

Catabolism

ApoB-100-mediated

uptake by LDL

receptor (~75% in

liver)HDL Phospholipids,

cholesteryl esters

5–15 Intestine,

liver, plasma

Transfer of cholesteryl

ester to VLDL and

LDL Uptake of HDL

cholesterol by

hepatocytes



3.4 Pathway for lipid transport

Each class of lipoprotein has a specific role in lipid transport, and there

are different pathways for exogenous and for endogenous lipids. The pathways are

distinguished by the main apoproteins that are ligands for the key receptors27.

3.4.1.Exogenous Pathway (From ingested food to intestine to peripheral cells and

Liver):

In the exogenous pathway, cholesterol and TGs absorbed from the ileum are

transported as chylomicrons, in lymph and then blood, to capillaries in muscle and

adipose tissue. Here, TG are hydrolysed by LPL, and the tissues take up the

resulting FFA and glycerol. The chylomicron remnants, still containing their full

complement of cholesteryl esters, pass to the liver, bind to receptors on

hepatocytes and undergo endocytosis. Cholesterol liberated in hepatocytes is

stored, oxidised to bile acids, secreted unaltered in bile, or can enter the endogenous

pathway.

3.4.2 Endogenous Pathway (From liver to peripheral tissues):

In the endogenous pathway cholesterol and newly synthesised TGs are

transported from the liver as VLDL to muscle and adipose tissue, where TG is

hydrolysed to fatty acids and glycerol these enter the tissues. During this process,

the lipoprotein particles become smaller but retain a full complement of

cholesterylesters. Consequently,they increase in density to IDL cholesterol and

ultimately become LDL particles.

Cells take up LDL by endocytosis via LDL receptors. Cholesterol can

return to plasma from the tissues in HDL particles. Cholesterol is esterified with

long-chain fatty acids in HDL particles and the resulting cholesteryl esters are

transferred to VLDL or LDL particles by a transfer protein present in the plasma

known as CETP. Lp(a) contains a unique [apo(a)], with structural similarities to

PLG. Lp(a) competes with and inhibits the binding of PLG to its receptors on

the endothelial cell. PLG is normally the substrate for PLG activator, which is

secreted by and bound to endothelial cells, generating the fibrinolytic enzyme

plasmin.



Reverse Cholesterol Transport

Reverse cholesterol transport refers to the process by which cholesterol is removed

from the tissues and returned to the liver. HDL is the key lipoprotein involved in

reverse cholesterol transport and the transfer of cholesteryl esters between lipoproteins.

The smallest and most dense lipoprotein particle is HDL. HDL is formed through a

maturation process where nascent HDL is secreted by the liver and intestine and

proceeds through a series of conversions (known as the "HDL cycle") to attract

cholesterol from cell membranes and free cholesterol to the core of the HDL particle,

although the exact mechanism for this not yet clear. It has been suggested that the

action of cholesteryl ester transfer protein transforms HDL into a TAG-rich particle that

interacts with hepatic-triglyceride lipase. Cholesterol ester-rich HDL may also be taken

up directly by the receptors in the liver. Another mechanism may be that cholesterol

esters are delivered directly to the liver for uptake without catabolism of the HDL

cholesterol particle.

Fig 3.9 Exogenous and Endogenous pathway for lipid Transport in Liver



Table-3.7 Enzymes of importance in lipid transport & metabolism28

Enzymes Functions

Lipoprotein lipase

Hydrolysis of TG rich particles

some phospholipase activity activated

by APO C-II

Hepatic lipase

Hydrolysis of Tri-, Di- and mono acyl-

glycerol’s, acyl-CoA thioester and

phospholipids conversion of HDL2 to

HDL1 activated by apoA- II

Pancreatic lipase

Hydrolysis of FAs at positions 1 and

3 of emulsified TGs in the intestine.

Lecithin cholesterol Acyl

transferase LCAT

Catalysis of lecithin with cholesterol to

give lysolecithin and cholesteryl ester

activated by apo A-I and apo c -I.

Pancreatic cholsterolesterase Esterification of cholesterol in the

intestinal lumen

Acyl co A-cholesterol acyl

transferase ACAT

Esterification of cholesterol with in the cells

Cholesterol ester transfer protein CETP

Transfers esterified cholesterol from

HDLs to VLDLs and LDLs.

HMG Co A reductase Rate limiting enzyme of cholesterol synthesis



3.5 HYPERLIPIDAEMIA AS A RISK FACTOR FOR CHD

From available epidemiological and scientific data, dyslipidaemia has been

identified as one of the main risk factors for CHD. Specific lipid abnormalities

implicated are :

3.5.1 Elevated LDL-C levels29

LDL-C has been shown to be atherogenic in epidemiological studies. There

is a direct relationship between levels of LDL-C (or TC) and the rate of new

onset CHD in men and women who were initially free from CHD. In people

with established CHD, elevated LDL-C correlates with recurrent cardiac events.

There is a near absence of clinical CHD in populations with very low levels of

serum cholesterol throughout their life (TC < 3.89 mmol/L or LDL-C 2.6 mmol/L)

The risk for CHD appears to increase progressively above these levels. At levels

of LDL-C above 3.4 mmol/l, atherogenesis proceeds at a significant rate

particularly in the presence of other major risk factors.

3.5.2 Low HDL-C levelsThere is substantial data linking a low HDL-C with increased risk of CHD. A 1

% decrease in HDL-C is associated with 2-3 % increase in CHD risk. Clinical trial

data suggests that raising HDL-C will reduce risk for CHD.30

3.5.3Elevated TG levelsRecent data show that raised triglycerides are independent risk factors for

CHD. This suggests that some TG-rich lipoproteins are atherogenic. Weight

reduction and drug therapies reduce remnant lipoproteins (fibrates, nicotinic acidand

statins) and are accompanied by reduced risk for CHD .31

3.6 Atherosclerosis

The word atherosclerosis is derived from greek words Athero(gruel or paste)

and sclerosis(hardness). Atherosclerosis maybe defined as degenerative changes in

intima of medium and large arteries. The degeneration includes accumulation of lipis,

complex carbohydrates, blood and blood products, cellular waste products and is

accompanied by formation of fibrous tissue and calcium deposits in intima of blood

vessels.

3.6.1 Role of lipids in atherogenic process32

Framingham et al and from other studies demonstrate that risk of developing



cardiovascular disease is related to degree of TC and LDL elevation in graded and

continous fashion. There is an evidence implicating role of hypercholesterolemia in

atherogenic process is that dominant lipids in atheromatus plaques are cholesterol and

cholesterol esters. Genetic defects in lipoprotein uptake and lipoprotein metabolism

that cause hypolipoprotenemia are associated with accelerated atherosclerosis.

Lowering serum cholesterol by diet or drugs slows the rate of progression of

atherosclerosis, causes regression of some plaques and reduces risk of cardiovascular

diseases.

3.6.2 Atherogenic index

Lipid profile consists of a group of biochemical tests often used in predicting,

diagnosing and treating lipid-related disorders including atherosclerosis. Abundant

evidence has accumulated relating the concentrations of lipids (total cholesterol and

triglycerides) and their associated blood transporting lipoproteins (HDL-C, LDL-C,

VLDL-C) with the occurrence of atherosclerosis in general and coronary artery disease

(CAD) in particular. A lot of work has been done on the relationship between TG and

HDL-C, and it has been shown that the ratio of TG to HDL-C was a strong predictor of

myocardial infarction. Universally, atherogenic index of plasma (AIP) calculated as log

(TG/HDL-C) has been used by some practitioners as a significant predictor of

atherosclerosis.33

Atherogenic index = log(TG/HDL-C)

3.7 PHARMACOTHERAPY OF HYPERLIPIDEMIAS :

Diet and lifestyle changes can help treat hyperlipidemia. In some cases,

a combination of diet and lifestyle changes and medication may be required.

3.7.1 Diet Changes

Limit sugar and carbohydrate in diet (i.e., diabetic diet)

Eat a diet low in total fat, saturated fat, and cholesterol.

Reduce or eliminate the amount of alcohol drink.

Increase consumption of high-fiber foods such as fruits, vegetables, beans,

and whole grains.

3.7.2 Lifestyle Changes34

Obtain and maintain optimal body weight.

Smoking cessation



Exercise regularly.

Get your doctor's okay before starting exercise, because people with

hyperlipidemia may already have hardening of the arteries or heart disease,

which increase the risk of a heart attack or death while exercising.

3.7.3 Medications:When dietary therapy and exercise cannot reduce triglyceride

levels to normal values, medication should be considered.

3.8. Drugs used in Hyperlipidemia

The five major pharmacological classes of drugs routinely used in the

treatment are

1. Statins

2. Fibrates

3. Bile acid sequestrants

4. Cholesterol absorption inhibitors

5. Nicotinic acid derivatives

Although many efficacious lipid-lowering drugs exist, none is effective for all

lipoprotein disorders and all such agents are associated with some adverse effects.

Diet should be continued to achieve the full potential of the drug regimen.

3.8.1 Statins (3-hydroxy-3-methylglutaryl-coenzymeA(HMG-CoA)reductase

inhibitors):

These compounds are structural analogs of HMG-CoA and are the most

effective and best-tolerated agents for treating hyperlipidemia. Lovastatin,

atorvastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin belong to this

class.36

Mechanism of Action: Statins affect blood cholesterol levels by inhibiting hepatic

cholesterol synthesis by reducing the conversion of HMG-CoA to mevalonate. Statins

inhibit an early and rate-limiting step in cholesterol biosynthesis, which results in

increased expression of the LDL receptor gene. In response to the reduced free

cholesterol content within hepatocytes, membrane-bound Sterol Regulatory Element-

Binding Proteins (SREBPs) are cleaved by a protease and translocated to the nucleus.

The transcription factors then bind the sterol-responsive element of the LDL receptor



gene, enhancing transcription and increasing the synthesis of LDL receptors.

Degradation of LDL receptors also is reduced. The greater number of LDL receptors

on the surface of hepatocytes results in increased removal of LDL from the blood,

thereby lowering LDL levels.

Adverse Effects: Major adverse effect associated with statin use is myopathy but

the risk of myopathy and rhabdomyolysis increases in proportion to plasma statin

concentrations.

3.8.2 Fibric acid derivatives

These cause a marked reduction in circulating VLDL, and hence TG, with a

modest reduction in LDL and an approximately 10% increase in HDL. Benzafibrate,

ciprofibrate, g em f i b r o z i l , fenofibrate come under this class.

Mechanism of Action: T hey are agonists for a subset of lipid-controlled gene

regulatory element, Peroxisome proliferator-activated receptors (PPARα), which are

members of the superfamily of nuclear receptors, the main effects are to increase

transcription of the genes for lipoprotein lipase, apolipoproteinA1 and A5. They

increase hepatic LDL uptake.

Adverse Effects: Myositis is unusual but can be severe, with myoglobinuria and

acute renal failure.37

3.8.3 Bile acid sequestrants

Cholestyramine and colestipol are among the oldest of the hypolipidemic

drugs, and they are probably the safest, since they are not absorbed from the intestine.

Mechanism of Action: The bile-acid sequestrants are highly positively charged and

bind negatively charged bile acids. Because of their large size, the resins are not

absorbed, and the bound bile acids are excreted in the stool. Since over 95% of bile

acids are normally reabsorbed, interruption of this process depletes the pool of bile

acids and hepatic bileacid synthesis increases. As a result, hepatic cholesterol

content declines, stimulating the production of LDL receptors. The increase in hepatic

LDL receptors increases LDL clearance and lowers LDL levels.38

Adverse effects: A s resins are not absorbed, systemic toxicity is low but

gastrointestinal symptoms-especially diarrhoea are common and dose-related.


mk:@MSITStore:D:/Suman%20M%20pharm%20thesis/BOOKS/Rang_and_Dales_Pharmacology__6th_Ed_2007_0443069115.chm::/www.studentconsult.com/content/bookcontent.cfm@id=hc020007.htm#%23


3.8.4 Cholesterol absorption inhibitors: It is one of a group of azetidinone

cholesterol absorption inhibitors, and is indicated as an adjunct to diet

and statins in hypercholesterolaemia.39

Mechanism of Action: Ezetimibe inhibits a specific transport process in jejunal

enterocytes, which take up cholesterol from the lumen.

Adverse effects: Ezetimibe is generally well tolerated but can cause diarrhoea,

abdominal pain, headache, rash and angio-oedema.

3.8.5 Niacin (Nicotinic Acid) derivatives :

It affects virtually all lipid parameters. Niacin decreases VLDL and LDL

levels and Lp(a). It often increases HDL levels significantly. It is given adjunct

to a statin and diet in dyslipidemia or when a statin is contraindicated.

Mechanism of Action: In adipose tissue, niacin inhibits the lipolysis of TGs by

hormone sensitive lipase, which reduces transport of FFA to the liver and

decreases hepatic triglyceride synthesis.

Table-3.8 Classification of antihyperlipidemic drugs39

Drug Class Lipid Effects Side Effects Contraindications

HMG-CoAreductase Inhibitors (statins)

LDL-C - 18-55%HDL-C - 5-15%TG - 7-30%

-Myopathy-Increased liver enzymes

Absolute: -Active or chronic liver disease Relative: -Concomitant use of certain drugs*

Fibric-Acid Derivatives (Fibrates)

LDL-C - 5-20% HDL-C - 10-35% TG - 20-50%

-Dyspepsia-Gallstones-Myopathy

Absolute: -Severe hepatic disease-Severe renal disease



Bile-Acid Sequestrants (Resins)

LDL-C - 15-30% HDL-C - 3-5%

-GIT distress-Constipation-**Decreased absorption of certain

drugs63,64,65,66

Absolute: -Dysbeta- lipoproteinemia-Tg > 4.5 mmol/l Relative: Tg > 2.3 mmol/l

Nicotinic Acid (Niacin)

LDL-C - 5-25 HDL-C - 15-35% TG - 20-50%

-Flushing-Hyperglycemia-Hyperuricemia (or gout)-Upper-GIT distress-Hepatotoxicity

Absolute: -Chronic-liver disease-Severe Gout Relative: -Diabetes (high doses only )-Hyperuricemia-Peptic-Ulcer Disease

Cholesterol Absorption Inhibitors ***

LDL-C - 18-25% HDL-C - 3-5% TG - 8-14%

-Headache-Abdominal pain-Diarrhea

3.8.6 Role of plant sterols in controlling cholesterol

Phytosterols (referred to as plant sterol and stanol esters) are a group of

naturally occurring compounds found in plant cell membranes. While cholesterol is

sterol of mammalian cells, phytosterols are sterols produced by plants. Plant sterols are

similar to their structure to cholesterol they posses ethyl or methyl group in their side

chain. plant derived sterols have been showed to decrease cholesterol for more than

fifty years. plant sterols have now become a part of public health strategy along with

normal medication. Due to structural similarity to cholesterol plant sterol impair

intestinal absorbtion of cholesterol. The ability of plant sterols to displace cholesterol

from micelles in small intestine is one mechanism of action of plant sterols. It appears

that esterification of sterol increases their solubility in fat and their in lowering LDL-

Cholesterol.

The useage of plant sterols has been recommended by both American heart

association and National cholesterol education program panel as adjuvant in lowering

lipid levels.40Plant sterols and stanols are substances that occur naturally in small

amounts in many grains, vegetables, fruits, legumes, nuts, and seeds. Since they have

powerful cholesterol-lowering properties, manufacturers have started adding them to

foods. You can now get stanols or sterols in margarine spreads, orange juice, cereals,



and even granola bars. As part of a heart-healthy eating plan, consuming phytosterols in

recommended quantities has been shown to lower total cholesterol up to 10 percent and

LDL or “bad” cholesterol up to 14 percent. This reduction is in addition to other

cholesterol-lowering strategies you may have initiated, such as eating more heart

healthy or taking a cholesterol-lowering statin. The effectiveness of phytosterols is so

strong that The National Cholesterol Education Program recommends people with high

cholesterol consume 2 grams of phytosterols each day.

The Food and Drug Administration (FDA) has even approved a health claim on

phytosterols, which states: “Foods containing at least 0.65 gram per serving of

vegetable oil plant sterol esters, eaten twice a day with meals for a daily total intake of

at least 1.3 grams, as part of a diet low in saturated fat and cholesterol, may reduce the

risk of heart disease.”

Table-3.9 Screening models for Antihyperlipidemic agents

S.no Model Mechanism

1. Diet

a)Atherogenic41

b)Cafeteria

Higher availability of Acetyl co-A

stimulates cholesterogenesis synthesis.

2. Triton43 Increasing hepatic cholesterol synthesis

and by decreasing cholesterol excretion

3. Carbohydrates42 A hypertriglyceridemic effect is seen due

to hepatic overproduction of VLDL and

induction of lipogenic enzymes via dietary

sucrose

4 Alcohol Generate free radicals which induce

oxidative stress that have potential to raise

blood cholesterol and triglycerides.

5 Isoproterenol44 By increasing lipid peroxidation induced

free radicals that causes cholesterol

synthesis

6 Genetic models

a)Monosodium

MSG reported to produce lesions of

arcurate nucleus in h followed by



glutamate(MSG)45

b)Hereditary

hypercholesterolemia in rats

and rabbits

hypoplastic-hypertri=ophic obesity.

b)By decreasing rate of catabolism of

chylomicrons and LDL.

7 Iron rich diet and copper

deficiency46

Copper deficiency results in inadequate

antioxidant mechanism that results in liver

iron retension.This in combination of diet

results in generation of free radicals that

leads to increased cholesterol synthesis.

8 Polaxomer-407 induced47 By inhibition of lipoprotein lipase

9 Intravenous lipid tolerance

test43

Drugs possessing lipolytic activity can be

determined

10 Influence on lipoprotein

lipase43

Inhibition of lipoprotein lipase decrease

degradation of lipids

11 Diabetic models48

a)Alloxan induced

b)Streptozocin induced

By selective degradation of beta cells

inhibit insulin secretion that alters

carbohydrate,lipid metabolism

3.9 Experimental models of hyperlipidemia

3.9.1 High fat diet induced hyperlipidemia41

Principle-

The model is based on fact that high fat diet causes Higher availability of

Acetyl co-A stimulates cholesterogenesis synthesis.

Procedure -

In rats hyperlipidemia can be induced by daily oral administration of fat diet

containing 2%cholesterol, 2%cholic acid, choline chloride suspended in peanut oil

for a period of 26 days. Test compounds and standard drug administered after

induction or may be administered simultaneously. High fat diet causes increased

lipid profile. The cholesterol, triglycerides, HDL-C, LDL-C,VLDL-C are compared

with positive control to asses antihyperlipidemic activity.

3.9.2 TritonX-100 induced hyperlipidemia43

Principle-



The model is based on fact that triton,non ionic surfactant (iso octyl

polyoxyethylene phenol/Tyloxipal) to rats results in biphasic elevation of lipid

levels.

Procedure-

Phase I- It is is thought to be due to increased hepatic synthesis of cholesterol

which reaches to elevated lipid levels at end of 48hr through the ability to interfere

with uptake of lipids by tissues.

Phase II- In this phase the elevated lipid levels reach maximum by end of 72hrs

due decreased cholesterol secretion. Drugs that can alter cholesterol excretion can be

assessed. The biphasic nature of Triton induced hyperlipidemia is helpfull in

understanding mode of action of antihyperlipidemic drugs.

3.9.3 Fructose indued hyperlipidemia42

Principle –

The model is based on fact that dietary fructose causes hepatic overproduction

of VLDL and induction of lipogenic enzymes.

Procedure-

Carbohydrate, fructose plays an important role in pathogenesis of experimental

hypertriglyceridemia and hyperinsulinemia. Adverse effect of fructose on

insulin sensitivity in rats is well established. In rats hypertriglyceridemia can be

induced by administering fructose(60%) for 30 days. Test drug and standard

drugs administerd simultaneously or after induction for 2 weeks. Later lipid

profile of all animals measured and compared with positive control.

3.9.4 Intravenous lipid tolerance test in rats50,51

Purpose and rationale

Intravenous injection of a lipid emulsion results in an increase of triglycerides in

serum. The lipolytic activity an be determined by measuring lipid elimination.

procedure

Male Wistar rats weighing 200–240 g are treated daily with various doses of the

test compound or the vehicle over a period of 5 days. On the fifth day, two

hours after the last administration of the test compound, the animals are

anesthetized with 125 mg/kg sodium hexobarbital i.p. Then they are injected

intravenously with 2 ml/kg of a 10% lipid emulsion (Intralipid® Vitrum,

Hausmann AG, St. Gallen, Switzerland). Prior to the injection and 10, 20, 30,



and 40 min thereafter blood is withdrawn by retroorbital puncture for

determination of triglycerides.

Table-3.10 Medicinal plants having Antihyperlipidemic activity52

Plant Family Part Mechanism

Corriandrum sativum Umbelliferae Leaves,seeds

By decreasing update

and increasing break

down of lipid

Trichilia connaroides Meliaceae LeavesBy interfering with

cholesterol biosynthesis

Curcuma longa Zinziberaceae TuberBy increasing

cholesterol catabolism

Nardostachys

jatamansiValerianaceae Whole plant

By increasing

cholesterol catabolism

Achyranthus aspera Amaranthaceae Aerial parts

By rapid excretion of

bile acids causing low

absorption of cholesterol

Cassia tora Caesalpinaceae seedsBy inhibitinf Acetyl co-

A activity.

Phaseolus

aconitifoliusLeguminosae Seeds

By increasing LDL

catabolism and

decresing LDL synthesis

Allium sativum Liliaceae BulbsBy enhancing

cholesterol degradation

Enicostemma littorale Gentianaceae Whole plantBy inhibiting HMGCoA

activity

Pterocarpus

marsupiumFabaceae Heart wood Not known

Trigonellafoenum

graecumFabaceae Seeds Not known

Phyllanthus niruri Euphorbiaceae Whole plant By enhancing LCAT



activity

Paeonia lactiflora Ranunculaceae Roots Not known

Glycine tomentella Leguminosaes Roots Not known

3.10 Plant profile

Botanical name : Glycosmis pentaphylla

Taxonomical classification

Kingdom : Plantae

Order : Sapindales

Family : Rutaceae

Subfamily : Aurantioideae

Genus : Glycosmis

Species : Glycosmis pentaphylla

Synonyms : Glycosmis arborea

3.9.1 Vernacular names in India53

English : Orange berry

Hindi : Ban nimbu

Sanskrit : Asvasakhotha

Oriya : Gonjipandu

Telugu : Sirna tulasi

sTamil : Konchi

Malayalam : Kurumpannal

3.9.2 Common names in other countries53

Chinese : Shi ling ju.



English : Gin berry

French : Glycosmisier de Cochinchine

3.9.3 Geographical distribution

Glycosmis pentaphylla(Rutaceae) is a medium annual shrub native to tropical Asia and

distributed in the tropical and subtropical regions.

Fig- 3.10 Glycosmis pentaphylla palnt



Fig –3.11 Glycosmis pentaphylla stem

Morphological characteristics

Glycosmis pentaphylla is a shrub growing 1 to 5 meters high. Leaves usually have 3 to

5 pinnately arranged leaflets, though these are sometimes reduced to one or two, all

forms being often found on the same plant. Leaflets are oblong-lanceolate to lanceolate,

5 to 18 centimeters long, and 2 to 7 centimeters wide. Flowers are small, white, about 6

millimeters in diameter, borne in axillary, solitary or paired, interrupted, narrow,

cymose panicles which are 5 centimeters long or less. Fruit is fleshy, pink or reddish,

rounded, 1 centimeter in diameter, and contains a single nearly spherical seed which is

about 4 millimeters in diameter. Mesocarp is fleshy and sweet.

3.9.4 CHEMICAL CONSTITUENTS54 :

Leaves : Contains quinolone alkaloid-glycolone.

Flowers: Contains alkaloids and an amide, alkaloids-arborine, arborinine,

skimmianine, glycorine, glycosmicine benzamide-2-methylamino. Also contains

carbazole alkaloid-mupamine

Roots: Contains Dictamine, γ-fagarine, skimmianine, β-sitosterol, coumarin,

stigmasterol, myricylalcohol, base glyborine, triterpenes-arborinolA,arborinolB,

arborine, arborinine,carbazolealkaloid- Glycozolinol,Glycozolicine,3-formylcarbazole



and glycosinine,glycozolidol.Root bark contains Acridone alkaloids-Noracronycine, de-

methylacronycine and e-N-methylnoracronycine.

3.9.5 Traditional uses:54

The plant is used in indigenous medicine for cough, rheumatism, anaemia and

jaundice.

The juice of the leaves ,which is bitter, is used in fever, liver complaints and as

vermifuge.

A paste of the leaves with ginger is applied in eczema and skin infections.

A decoction of the root is given for facial inflammations.

3.9.6 LITERATURE REVIEW OF ACTIVITIES DONE ON PLANT

1. Wang J, DiY, Yang X, Li S, Wang Y , Hao X, in 2006 reported ,

Hydroquinone diglycoside acyl esters from the stems of Glycosmis pentaphylla .

Four hydroquinone diglycoside acyl esters, glypentosides A–C (1–3) and

seguinoside F (4), were isolated from the stems of Glycosmis pentaphylla.56

2. Pacher T, Bacher M , Hofer O , Greger H , in 2001 reported, Stress induced

carbazole phytoalexins in Glycosmis species . Induced formation of a series of

carbazole alkaloids was observed in leaves of Glycosmis parviflora and

G.pentaphylla after wounding, UV-irradiation, and particularly after inoculation

with the fungus Botrytis cinerea. Detailed experiments with marked infection areas

confirmed the restricted accumulation of carbazole derivatives which could not be

detected in non-infected areas of the same leaf.57

3. Quader MA., Nutan MTH , Rashid MA , in 1999 reported , Antitumor

alkaloid from Glycosmis pentaphylla . Arborinine, an acridone alkaloid obtained

from Glycosmis pentaphylla, exhibited significant inhibition of crown gall tumors

produced by Agrobacterium tumefaciens in a potato disc bioassay58.



4. Muthukrishnan J, Seifert K, Hoffmann KH , Lorenz MW,in 1999 reported,

Inhibition of juvenile hormone biosynthesis in Gryllus bimaculatus by Glycosmis

pentaphylla leaf compounds. The EtOAc fraction of Glycosmis pentaphylla leaf

extract inhibits the juvenile hormone III-biosynthesis in vitro of corpora allata

from 3 day old females of the field cricket Gryllus bimaculatus. The bioactive

compound which is responsible for this activity was identified as the quinazolone

alkaloid arborine. This alkaloid showed also a larvicidal activity against the

mosquito Culex quinquefasciatus59

5. Bhattacharyya P, Chowdhury BK, in 1985 reported ,Glycolone, a quinolone

alkaloid from Glycosmis pentaphylla Glycolone, a quinolone alkaloid has been

isolated from the leaves of Glycosmis pentaphylla. The structure of the compound

has been established as 4,8-dimethoxy-3-(3-methyl but-2-enyl)-2-quinolone from

physical and chemical evidences.60

6. Bhattacharyya P, Chakrabartty PK , Chowdhury BK ,in 1985 reported,

Glycozolidol, an antibacterial carbazole alkaloid from Glycosmis pentaphylla.

Glycozolidol, a new carbazole alkaloid, has been isolated from the roots of

Glycosmis pentaphylla. Its structure has been established as 6-hydroxy-2-methoxy-

3-methylcarbazole on the basis of physical and chemical evidence. The compound

has been found to be active at some Gram-positive and Gram-negative bacteria.61

7. Mukherjee S, Mukherjee M, Ganguly SN , in 1983 reported , Glycozolinine, a

carbazole derivative from Glycosmis pentaphylla. A new carbazole derivative,

glycozolinine, was isolated from the seeds of Glycosmis pentaphylla. From

physical and chemical evidence its structure is 6-hydroxy-3-methylcarbazole.61

8. N. Jaya Raju et al. studied hepatoprotective activity of glycosmis pentaphylla

roots against ccl4– induced acute liver injury in rats. Golugu and Gongipadu

(Telugu) of ethyl acetate and methanolic extracts (100, 200 and 400 mg/kg) was

prepared and tested for its hepatoprotective effect against carbon tetrachloride

induced in rats. Treatment with ethyl acetate extract of Glycosmis pentaphylla

(Rutaceae) roots has brought back the altered levels of biochemical markers to the

near normal levels in the dose dependent manner. This was evident from



significant reduction in serum enzyme, SGOT, SGPT, ALP and Total bilirubin

Sand both the extracts were recorded with significant hepatoprotective activity62

9. Ramesh petchi r et al. studied anti-diabetic and anti-arthritic potential of

Glycosmis pentaphylla stem bark in fca induced arthritis and streptozotocin

induced diabetic rats. Graded doses of the ethonolic extract of Glycosmis

pentaphylla were administered to experimental arthriticand diabetic rats for

21days.Significant reductions in fasting blood glucose levels and inflammation

were observed in the respective diabetic and arthritic animals.63


3 Literature Review

Documents

Transcript of 3 Literature Review