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A Review Article on Hyperlipidemia: Types, Treatments and New Drug

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Biomedical & Pharmacology Journal Vol. 7(2), 399-409 (2014)

A Review Article on Hyperlipidemia:

Types, Treatments and New Drug Targets
GHASSAN F. SHATTAT

College of Science and Health Professions,

King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

http://dx.doi.org/10.13005/bpj/504

(Received: October 30, 2014; accepted: December 11, 2014)

ABSTRACT

Hyperlipidemia is a medical condition characterized by an increase in one or more of the

plasma lipids, including triglycerides, cholesterol, cholesterol esters, phospholipids and or plasma
lipoproteins including very low-density lipoprotein and low-density lipoprotein along with reduced
high-density lipoprotein levels. This elevation of plasma lipids is among the leading risk factors
associated with cardiovascular diseases. In the meantime, statins and fibrates remain the major
anti-hyperlipidemic agents for the treatment of elevated plasma cholesterol and triglycerides
respectively, with the price of severe side effects on the muscles and the liver. The present review
focuses mainly on the types of hyperlipidemias, lipid metabolism, treatments and new drug targets
for the treatment of elevated lipid profile. Many agents such as lanosterol synthase inhibitors,
squalene epoxidase inhibitors, diacyl glycerol acyl transferase inhibitors, ATP citrate lyase inhibitors
have shown a promising potential in the treatment of hyperlipidemia in clinical trials.

Key words: Hyperlipidemia, Lipid metabolism, Hypolipidemic drugs, Squalene epoxidase inhibitors,
Lanosterol synthase inhibitors, Diacyl glycerol acyl transferase inhibitors.

INTRODUCTION between IHD and the high mortality rate. Further

more elevated plasma cholesterol levels cause
Hyperlipidemia is considered one of the more than four million deaths in a year6.
major risk factors causing cardiovascular diseases
(CVDs).CVDs accounts for one third of total deaths Atherosclerosis is a process of arteries
around the world, it is believed that CVDs will turn hardening due todeposition of cholesterol in the
out to be the main cause of death and disability arterial wall which causes narrowing of the
worldwide by the year 20201,2. arteries.Atherosclerosis and atherosclerosis-
associated disorders like coronary, cerebrovascular
Hyperlipidemia is an increase in one or and peripheral vascular diseases are accelerated
more of the plasma lipids, including triglycerides, by the presence of hyperlipidemia 7.
cholesterol, cholesterol esters and phospholipids
and or plasma lipoproteins including very low- Hyperlipidemiarelates to increased
density lipo protein and low-density lipoprotein, and oxidative stress causing significant production of
reduced high-density lipoprotein levels3,4. oxygen free radicals, which may lead to oxidative
modifications in low-density lipoproteins, which
Hypercholesterolemia and present a significant function inthe initiation and
hypertriglyceridemia are the main cause of progression of atherosclerosis and associated
atherosclerosis which is strongly related to ischemic cardiovascular diseases3.
heart disease (IHD)5. There is a strong relation
400 SHATTAT, Biomed. & Pharmacol. J., Vol. 7(2), 399-409 (2014)

Plasma lipoproteins Hepatic lipase (HL)

Composition and structure HL is a multifunctional protein that regulate
Lipoproteins are macro molecules lipoprotein metabolism. It is synthesized by
aggregate composed of lipids and proteins; this hepatocytes and found in adrenalgl and and ovary.
structure facilitates lipids compatibility with the HL hydrolyzes phospholipids and triglycerides of
aqueous body fluids. plasmalipo proteins. In addition HL affects cellular
lipid delivery by facilitating lipoprotein absorption
Lipoproteins composed from non- by cell surface receptors and proteoglycans12.
polarlipids(triglycerides and cholesteryl esters),
polar lipids(phospholipids and unesterified Lecithin cholesterol acyl transferase (LCAT)
cholesterol) and specific proteins known as apolipo Lecithin cholesterol acyltransferase,is a
proteins.Apolipoproteinsare amphiphilic proteins crucial enzyme in the metabolism of HDL. It converts
that bindto both lipids and the plasma8. free cholesterol into cholesteryl esters which then
sequestered into the core of lipoprotein andfinally
Lipoproteinclassification making mature HDL13.
Chylomicrons (CM),verylow-
densitylipoproteins (VLDL), low-density Cholesteryl ester transfer protein (CETP)
lipoproteins(LDL), intermediate-density Cholesteryl ester transfer protein (CETP),
lipoproteins (IDL) and high-densitylipoproteins also called plasma lipid transfer protein, is a
(HDL) are the five classes of lipoproteins present hydrophobic plasma glycoprotein that accelerates
in plasma.These classes areheterogeneous; they the transferring of esterified cholesterol esters (CE)
have different composition, size, and density8. from HDLs to chylomicrons, VLDL and LDL, in
exchange for triglyceride. ACETP deficiency is
As the triglyceride and cholesteryl ester linked to increased HDL levels and decreased LDL
contents of the core increases the lipoprotein size levels14.
increases,the density of lipoproteins increase also
proportionally to their protein contents, and Microsomal triglyceride protein (MTP)
contrariwise to their lipid contents9. Microsomal triglycerideprotein (MTP) is a
lipid transfer protein catalyzesthe transfer of neutral
Lipoprotein Function lipids, triglycerides and cholesterol esters between
Plasma lipoproteins are important for lipid membrane of the lumen of microsomes isolated
solubilization in order to transporttriglycerides, an from the liver and intestinal mucosa. Microsomal
importantenergy source, which synthesized and triglycerideprotein is an essential protein in the
absorbed to places of utilization and storage; and assembly of apo B containing lipoproteins. Now it
to transport cholesterol between different places of is known that MTP is important in the biosynthesis
absorption, synthesis, catabolism, and of glycolipid presenting moleculesand the
elimination10. regulation of cholesterol ester biosynthesis15.

Enzymes involved in lipoprotein metabolism Acyl Co-A transferase (ACAT)

Lipoprotein lipase (LPL) Acyl Co-A transferase (ACAT) is
LPL is a multifunctional enzyme membrane-bound protein that useslong-chain fatty
expressed on endothelial cells in the heart, muscle, acyl-CoA and cholesterol as substrates to produce
adipose tissue, macrophages and lactating cholesteryl esters. ACAT plays significant roles in
mammary glands. LPL plays a critical role in the cellular cholesterol homeostasis in various tissues
hydrolysis of triglyceride (TG) into two free fatty acids and prevents the toxic accumulation of excess
and monoacylglycerol. Besides LPL helps in the cholesterol in a cell. Further more,the importance
receptor-mediated lipoprotein uptake of of ACAT arises from its crucial role in the assembly
chylomicron remnants, cholesterol-rich along with the secretion of apolipoprotein-B
lipoproteins, and free fatty acids11. containing lipoproteins in the liver and intestines16.
 SHATTAT, Biomed. & Pharmacol. J., Vol. 7(2), 399-409 (2014) 401

Lipid metabolism factor is mainly poor diet in which fat intake form
Almost all the dietary fats are absorbed saturated fat and cholesterol exceeds 40 percent
from the intestinal lumen into the intestinal lymph of the total calories uptake20.
and packed into chylomicrons. These lipoproteins
move into the blood stream where they got Symptoms of hyperlipidemia
hydrolyzed by endothelial lipoprotein lipase which Generally hyperlipidemia does not have
hydrolyzes the triglyceride into glycerol and non- any obvious symptoms but they are usually
esterified fatty acids. After which the chylomicron discovered during routine examination or until it
remnants are absorbed in the liver and packaged reaches the danger stage of a stroke or heart attack.
withc holesterol, cholesteryl esters and ApoB100 Patients with high blood cholesterol level or patients
to form VLDL. After the release of VLDL into the with the familial forms of the disorder can develop
blood stream it will be converted into IDL by the xanthomas which are deposits of cholesterol may
action of lipoprotein lipase and hepatic form under the skin, especially under the eyes. At
lipase,where phospholipids and apolipoproteins the same time, patients with elevated levels of
transferred back to HDL. Furthermore, after the triglycerides may develop numerous pimple-like
hydrolysis by hepatic lipase, IDL will be converted lesions at different sites in their body19.
to LDLand loss more apolipoproteins17.
Complications of hyperlipidemia
Peripheral cholesterol is returned to the Atherosclerosis: Hyperlipidemia is the
liver by reverse cholesterol transport pathway using most important risk factor for atherosclerosis, which
HDLs which are originally synthesized by the liver is the major cause of cardiovascular disease.
and released into the blood. In the blood, HDL Atherosclerosisis a pathologic process
cholesterol is esterified by LCAT to cholesteryl ester characterized by the accumulation of lipids,
and transferred to VLDL and chylomicrons to return cholesterol and calcium and the development of
to the liver through LDL receptor. Cholesteryl ester fibrous plaques with in the walls of large and
are transferred to LDL particles by CETP and then medium arteries21.
subjected to LDL-receptors mediated endocytosis.
Finally, cholesteryl esters are hydrolyzed to Coronary Artery Disease (CAD): Atherosclerosis,
cholesterol and extracted from the body as bile the major cause of coronary artery disease,
acid18. characterized by the accumulation of lipid and the
formation of fibrous plaques within the wall of the
Hyperlipidemia classification arteries resulting in narrowing of the the arteries
Hyperlipidemiain general can be classified to: that supply blood to the myocardium, and results in
Primary: it is also called familial due to a limiting blood flow and insufficient amounts of
genetic defect, it may be monogenic: a single gene oxygen to meet the needs of the heart. Elevated
defect or polygenic: multiple gene defects. Primary lipid profile has been connected to the development
hyperlipidemia can usually be resolved intoone of of coronary atherosclerosis22.
the abnormal lipoprotein patterns summarized in
table 119. Myocardial Infarction (MI): MI is a
condition which occurs when blood and oxygen
Secondary: it is acquired because it is supplies are partially or completely blocked from
caused by another disorder like diabetes, nephritic flowing in one or more cardiac arteries, resulting in
syndrome, chronic alcoholism, hypothyroidism and damage or death of heart cells. The occlusion may
with use of drugs like corticosteroids, beta blockers be due to ruptured atherosclerotic plaque. The
and oral contraceptives. Secondary hyperlipidemia studies show that about one-fourth of survivors of
together with significant hypertriglyceridemia can myocardial infarction were hyperlipidemic23.
cause pancreatitis20.
Ischemic stroke: stroke is the fourth
The main cause of hyperlipidemia leading cause of death. Usually strokes occur due
includes changes in lifestyle habits in which risk to blockage of an artery by a blood clot or a piece of
402 SHATTAT, Biomed. & Pharmacol. J., Vol. 7(2), 399-409 (2014)

atherosclerotic plaque that breaks loose in a small concentrations. Diallylthiosulfinate,a metabolite of

vessel within the brain. Many clinical trials revealed allicin, block the formation of 7-dehydrocholesterol
that lowering of low-density lipoprotein and total and reduced the production of cholesterol. Bis-(3-
cholesterol by 15% significantly reduced the risk of (4-nitrophenyl)prop-2-ene)disulfide, a new
the first stroke24. derivatives of diallyldisulfide, is effective in reducing
plasma total cholesterol27.
Drugs classes for hyperlipidemia
Since LDL is the major atherogeniclipo Side effects
protein, reduction of this lipoprotein would be Statins are frequently well tolerated with
expected to reduce atherosclerosis and therefore the most common adverse effects being transient
reduce cardiovascular adverse effects. In addition gastrointestinal symptoms, headache, myalgia and
to high LDL, presence of risk factors and CHD dizziness.These symptoms are more common with
should qualify initiating drug therapy along with life higher doses and may solve ifa different statin is
style changing. Monotherapy has been shown to used28.
be effective in treating hyperlipidemia, but
combination therapy may be required for a Statins also cause myopathy,
comprehensive approach. Currently, rhabdomyolsis and an increase serum
antihyperlipidemic drugs contain five major classes transaminase. These substances are harmful to the
(Table 2) that include statins, fibric acid derivatives, kidney and often cause kidney damage.
bile acid binding resins, nicotinic acid derivatives Additionally statins may cause cardiomyopathy29.
and drugs that inhibit cholesterol absorption20. Recent clinical trials showed that statin use has
been linked to anincrease in type 2 diabetes30.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-
CoA)reductaseinhibitors (statins). Bile acid sequestrants
This class includes (Lovastatin, Bile acid synthesis is the main pathway of
Simvastatin, Pravastatin, Fluvastatin, Atorvastatin cholesterolcatabolism in the liver; it has been
and Rosuvastatin). Statinsare broadly prescribed estimated that about 500 mg of cholesterolis
in the treatment of hypercholesterolemia, can converted daily into bile acids in the adult
achieve 20%–50% reductions in cholesterol levels humanliver. Bile acids are secreted into the intestine
and have been linked to the reduced incidence of and have an important role in facilitating the
coronary morbidity and mortality in high-risk absorption of fats from food31.
adults25.
Bile acid sequestrants include
Mechanism of action cholestyramine, colestipol, colestimide,and
Thesedrugs are structural analogues of colesevelam. Cholestyramine and colestipol are the
HMG-coenzyme Areductase. They act by inhibiting two bile acid sequestrants currently available.
the rate limiting enzyme (HMG-coenzyme Cholestyramineis a quaternary amine composed
Areductase) in the biosynthesis of cholesterol in of styrene and divinylbenzenepolymers.
the liver. By inhibiting this enzyme, statins Colestipolis a copolymer of diethylenetriamine and
significantly reduce plasma levels of total 1-chloro-2,3-epoxypropane32.
cholesterol (TC),LDL and ApoB. Mean while, statins
also cause a modest decrease in plasma Mechanism of action
triglycerides and a small increase in plasma level Bile acid sequestrants are positively
of HDL26. charged resins that bind to the negatively charged
bile acids in the intestine to form a large insoluble
Other HMG-CoA reductase inhibitors complex that not absorbed and so excreted in the
include the diallyldisulfide (DADS) and feces. Excretion is increased up to tenfold when
diallylthiosulfinate. DADS, is an organosulfur resins are given, resulting in greater conversion of
compound derived from garlic, has been shown to cholesterol to bile acids. Furthermore bile acid
reduce cholesterol synthesisby 10–25% at low sequestrants increase HDL levels33.
 SHATTAT, Biomed. & Pharmacol. J., Vol. 7(2), 399-409 (2014) 403

Side effects the nuclear transcription receptor, PPAR-α. They

Bile acid sequestrants are rarely used as increased the expression of lipoprotein lipase, apo,
initial therapy because of poor patient tolerance. and down-regulate apo C-III, an inhibitor of lipolysis.
Gastrointestinal disturbances are the most common Fibrates also increase the level of HDL cholesterol
complaints of the bile acid sequestrants include by increasing the expression of apo AI andapo AII35.
constipation, nausea, indigestion,bloating and
flatulence34. Increase hepatic fatty acid (FA) uptake and
reduction of hepatic triglyceride production.
On long-term therapybile acid Fibrates enhance the production of fatty
sequestering agents may cause osteoporosis due acid transport protein and acyl-CoA synthetase,
to calcium loss. They may aggravate which contribute to the increase uptake of fatty acid
hypertriglyceridemia by an unknown mechanism. by the liver and as a result in a lower availability of
Some vitamins minerals deficiencymay occur32. fatty acids for triglyceride production36.

Fibric acid derivatives(Fibrates) Increase removal of LDL particles.

Fibrates include clofibrate, gemfibrozil, Fibrate, appears to enhance LDL
fenofibrate, and bezafibrate, areawidely used class catabolism via the receptor-mediated pathway; LDL
of antihyperlipidemic agents, results in a significant particles became larger and more lipid rich and
reduction in plasmatriglycerides and a modest therefore had more affinity for receptors. Fibrates
reduction in LDL cholesterol. HDL cholesterol level also inhibits the formation of slowly metabolized,
increases moderately. Angiographictrials results potentially atherogenic LDL particles37.
showed that fibrates play an important role in
slowing the progression of coronaryatherosclerosis Increase in HDL production and stimulation of
and decrease the incidence of coronary artery reverse cholesterol transport.
disease. Fibrates increase apo A-I production in the
liver which leads to the observed elevation in
Mechanism of action plasma levels of apo A4 and HDL-cholesteroland
Data from studies in rodents and in a more effective reverse cholesterol transport38.
humans imply fourmain mechanisms of fibrates:
Side effects
Stimulation of lipoprotein lipolysis. Generally, fibrates are considered to be
Fibrates function primarily as ligands for well tolerated. Side effects may include

Table. 1: Fredrickson classification of primary hyperlipidemia19.

Type Disorder Cause Occurrence Elevated

plasma
lipoprotein

I Familial hyperchylomicronemiaOr Lipoprotein lipase Very rare Chylomicrons

Primary hyperlipoproteinemia deficiencyor Altered ApoC2
IIa Familial hypercholesterolemia LDL receptor deficiencyLess LDL
OrPolygenic hypercholesterolemia common
IIb Familial combined hyperlipidemiaDecreased LDL receptor Commonest LDL and VLDL
III Familial dysbetalipoprotenemia Defect in Apo E- 2 synthesis Rare IDL
and increased ApoB
IV Familial hypertriglyceridemia Increased VLDL production common LDL
and decreased excretion
V Endogenous hypertriglyceridemia Increased VLDL production Less VLDL and
and decreased LPL common chylomicrons
404 SHATTAT, Biomed. & Pharmacol. J., Vol. 7(2), 399-409 (2014)

gastrointestinal symptoms, myopathy, arrhythmia, fractional clearance of apo A-1 and increasing HDL
skin rashes and gallstones. Fibrates should be synthesis32.
avoided in patients with liver and renal dysfunction32.
Side effects
Nicotinic acid derivatives (Niacin) Niacin treatment has been plagued by low
Niacin,a water-soluble vitamin of type B, compliance rates. The most common side effects
is the oldest lipid lowering agent used totreat areintense cutaneous flush which affect more than
hyperlipidemia and proved to decrease three quarters of patients, itching, headache
cardiovascular morbidity and total mortality. It andsome patients experience nausea and
decreases total cholesterol, LDL cholesterol, abdominal discomfort. Niacin also elevates liver
triglycerides. enzymes.

Besides, niacin is the most effective Administering statins in combination with

therapy available for the treatment of low HDL levels niacin increases the incidence of rhabdomyolysis.
when used in a dose of (H-1 gm per day)39. Niacin also promotes glucose in tolerance and
hyperuricemia which precipitate a gout attack34.
Mechanism of action
Niacin inhibits hormone-sensitive lipase Selective cholesterol absorption inhibitor
which decreases triglycerides lipolysis the main (Ezetimibe)
producer of circulating free fatty acids. The liver The discovery and development of
usually uses these circulating fatty acids as a major ezetimibe, the first member of a group of drugs that
precursor for triacylglycerol synthesis. Therefore, inhibit intestinal absorption of phytosterols and
niacin inhibits VLDL secretion, in turn decreasing cholesterol, has improved the treatment of
production of LDL. hypercholesterolemia. It inhibits the absorption of
cholesterol from the small intestine without any
Furthermore, niacin treatment elevates effect on the plasma concentrations of the fat-
HDL cholesterol concentrationsby reducing the soluble vitamins40.
Table. 2: Drug therapy for hyperlipidemia20.
A combination of statins and ezetimibe can
Drugs Effects on lipids achieve a reduction in LDL cholesterol levels
by25%, compared to 6% attained by doubling the
Statins: statin dose41.
Lovastatin (10-80 mg) Decrease TG
Simvastatin (5-40 mg) Decrease LDL Mechanism of action
Atorvastatin (10-80 mg) Increase HDL Ezetimibe selectively inhibits absorption
Rosuvastatin (5- 20 mg) of cholesterol in the smallintestine, leading to a
Bile acid binding resins: TG generally decrease in the delivery of intestinal cholesterol to
noteffected the liver by blocking the Niemann–Pick C1-like 1
Cholestyramine (4-16 mg) Decrease LDL protein (NPC1L1), a human sterol transport protein.
Colestipol(5-30 mg) Increase HDL This causes an increase in the clearance of
Fibric acid derivatives: cholesterol from the blood42.
Gemfibrozil (1200 mg) Decrease TG
Bezafibrate (600 )mg Decrease LDL Side effects
Fenofibrate(200 mg) Increase HDL Ezetimibeis usually well tolerated; the most
Nicotinic acid derivatives Decrease TG common side effects include headache, abdominal
Niacin(2-6 gm) Decrease LDL pain and diarrhea. Ezetimibe appears to cause
Increase HDL elevations in liver function tests include elevations
Cholesterol absorption inhibitors: Decrease LDL in alanine transaminase and aspartate
Ezetimibe ( 10 mg ) Decrease transaminase43.
cholesterol
 SHATTAT, Biomed. & Pharmacol. J., Vol. 7(2), 399-409 (2014) 405

New potential targets and treatments proatherogenicapolipo protein B containing

Recently, many clinical trials revealed new lipoproteins, including VLDLs and LDLs.
potential agents with promising antihyperlipidemic Furthermore, most studies showed that there is
activity. In this section, some of these agents will be evidence that CETP may playa proatherogenic role
reviewed. by involving in reverse cholesterol transport and
support the idea that inhibition of CETP slows the
Acyl-CoA cholesterol acyl transferase progression of atherosclerosis48.
inhibitors(ACAT)
Acyl-CoA cholesterol acyl transferase Dalcetrapib and anacetrapib are novel
(ACAT) is the enzyme that catalyzes the conversion compounds in Phase III of clinical trials. Dalcetrapib
of intracellular cholesterol into cholesteryl esters. reduced CETP activity by 50% and elevated HDL
ACAT has two isomers, termed ACAT1 and ACAT2. cholesterol levels by 31% without affecting LDL
cholesterol levels49.
ACAT1 contributes to foam cell formation
in the arterial wall and the development of Squalene synthase inhibitors
atherosclerosis, so ACAT-1 inhibitors may Squalene synthase (SqS) catalyzes
haveantiatherogenic effect and ACAT-2 inhibitors farnesyl pyrophosphate to form squalene, Catalysis
mayplay an important role in reducing cholesterol by SqS is the first committed step in sterol synthesis,
absorption in the intestine. and one of these sterols is cholesterol.
Pharmacologists regard SqS inhibitors as promising
Avasimibe and Eflucimibe act by inhibiting lead compounds in the development of potential
ACAT, decrease plasma cholesterol levels and slow agents to treat hyperlipoproteinemia50.
the development of atherosclerosis44,45. Some of the
potent ACAT inhibitors which are currently in clinical It has been reported that after oral
development are naphthoqui none derivatives46. administration ofBMS-188,494,a potential inhibitor
of SqS,the plasma levels of cholesterol was reduced
Microsomal triglyceride transfer protein (MTP) in experimental rats 51 . Concurrently, YM-
inhibitors 53601,another inhibitor of SqS,reduces plasma
Microsomal triglyceride transfer protein cholesterol and triglyceride levels52.
(MTP) has multiple functions including transferring
neutral lipids between membrane vesicles, the Hydroxymethylglutaryl-CoA synthase inhibitors
biosynthesis of CD1, antigen-presenting molecules, HMG synthase catalyzes the chemical
as well as in the regulation of cholesterol ester reaction that converts acetyl-CoA and acetoacetyl-
biosynthesis. Therefore, inhibiting MTP causes CoA to 3-hydroxy-3-methylglutaryl-CoA. L-659,699
significant reductions in plasma triglycerides, LDL, is one of the compounds that have shown a
and VLDL cholesterol. These findings suggest that potential HMG synthase inhibitor activity52.
inhibitors of MTP might be useful for reducing the
atherogenic lipoproteinslevels15. ATP citrate lyase inhibitors
ATP citrate lyase (ACL)is the primary
A series of newly synthesized enzyme accountable for the synthesis of
phosphonate esters were evaluated for their effects cytosolicacetyl-CoA and oxaloacetate. Synthesis of
on MTP activity andthey exhibita potent inhibition cytosolicacetyl-CoA and oxaloacetate represent an
bothin vitro and in vivo. Data also suggest the important step in the synthesis of fatty acids and
potency oflomitapide (AEGR-733, formerly BMS- cholesterol. For this reason, inhibition of ACL is a
201038), a novel drug for hypercholesterolemia47. promising strategy in the treatmentof dyslipidemia53.

Cholesteryl ester transfer protein (CETP) Recently, Li et al. described that a chronic
inhibitors administration of BMS-303141, the leading inhibitor
CETP in liver facilitates the transfer of of the enzyme ACL in the 2-hydroxy-N-arylbenzene
cholesteryl esters from anti-atherogenic HDLs to sulfon amides class, in high-fat–fed mice reduced
406 SHATTAT, Biomed. & Pharmacol. J., Vol. 7(2), 399-409 (2014)

weight gain and decreased plasma cholesterol, Squaleneepoxidase inhibitors

triglycerides, and glucose54. Squalene epoxidaseis one of the rate-
limiting enzymes for the first oxygenation step in
Acyl coenzyme A: diacyl glycerol sterol bio synthesis. NB-598 competitively inhibits
acyltransferase (DGAT) squalene epoxidase andinhibits cholesterol
DGAT is a microsomal enzyme that joins synthesis56.
Acyl CoA to 1,2-diacylglycerol in the final step in
triglyceride bio synthesis. Two forms ofDGAT(DGAT- Lanosterol synthase inhibitors
1 and 2) have been identified. Several studies lanosterol synthase (LSS) Catalyzes the
showed that inhibition of DGAT1 is a good target in cyclization of (S)-2,3 oxidosqualene to lanosterol,
the treatment of hyperlipidemia. the initial sterol intermediate in the cholesterol
synthesis pathway. LSS inhibitors such as U18666A
The compound T863 is a potent inhibitor and Ro 48-8071 have a potential to decrease
for DGAT1 in vitro; it was shown that a two weeks plasma LDL cholesterol levels57.
treatment with compound T863 decreased serum
and liver triglycerides, and decreased serum
cholesterolin mice55.

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