Shattat One thousand. F. A Review Commodity on Hyperlipidemia: Types, Treatments and New Drug Targets. Biomed Pharmacol J 2014;7(2)

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Ghassan F. Shattat

College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi arabia.

DOI : https://dx.doi.org/10.13005/bpj/504

Abstract

Hyperlipidemia is a medical condition characterized by an increase in 1 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 loftier-density lipoprotein levels. This superlative of plasma lipids is among the leading gamble factors associated with cardiovascular diseases. In the meantime, statins and fibrates remain the major anti-hyperlipidemic agents for the handling of elevated plasma cholesterol and triglycerides respectively, with the toll of astringent 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 handling of hyperlipidemia in clinical trials.

Keywords

Hyperlipidemia; Lipid metabolism; Hypolipidemic drugs; Squalene epoxidase inhibitors; Lanosterol synthase inhibitors; Diacyl glycerol acyl transferase inhibitors

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Introduction

Hyperlipidemia is considered one of the major take chances factors causingcardiovascular diseases (CVDs).CVDs accounts for one third of total deaths around the world, information technology is believed that CVDs will turn out to be the main cause of decease and inability worldwide by the year 20201,2.

Hyperlipidemia isan increasein one or more than of the plasma lipids, including triglycerides, cholesterol, cholesterol esters andphospholipids and or plasma lipoproteinsincluding very low-density lipoprotein and low-density lipoprotein,and reducedhigh-density lipoprotein levelsthree,four.

Hypercholesterolemia and hypertriglyceridemia are the main causeof atherosclerosis which is strongly related to ischemic heart disease (IHD)v. In that location is a strong relation betwixt IHD and the high mortality rate. Furthermoreelevated plasma cholesterol levels crusade more than four million deaths in a year6.

Atherosclerosis is a process of arteries hardening due todeposition of cholesterol in the arterial wall which causes narrowing of the arteries.Atherosclerosis and atherosclerosis-associated disorderslikecoronary, cerebrovascular and peripheral vascular diseases are accelerated by the presenceof hyperlipidemia 7.

Hyperlipidemiarelates to increased oxidative stress causingsignificant production of oxygen free radicals, which may pb to oxidative modifications in low-density lipoproteins, which nowadays a significant function inthe initiation and progression of atherosclerosis and associated cardiovascular diseases3.

Plasma lipoproteins

Composition and structure

Lipoproteins are macromolecules aggregate equanimous oflipids andproteins; this structure facilitates lipids compatibility withthe aqueous body fluids.

Lipoproteinscomposed from not-polarlipids(triglycerides and cholesteryl esters),polar lipids(phospholipids and unesterified cholesterol)and specific proteinsknown every bit apolipoproteins.Apolipoproteinsare amphiphilic proteins that bindto both lipids and the plasma8.

Lipoprotein classification

Chylomicrons (CM),verylow-densitylipoproteins (VLDL), low-density lipoproteins(LDL), intermediate-density lipoproteins (IDL) and high-densitylipoproteins (HDL) are the 5 classes of lipoproteins present in plasma.Theseclasses areheterogeneous;they have different limerick, size, and densityeight.

As the triglyceride andcholesteryl ester contentsof the core increases the lipoprotein size increases,the densityof lipoproteins increasealso proportionally to their protein contents, andcontrariwise to their lipid contents9.

Lipoprote in Function

Plasma lipoproteins are important for lipid solubilization in gild to transporttriglycerides, an importantenergy source,which synthesized and absorbedto places of utilization and storage;and to ship cholesterol between unlike placesof absorption, synthesis, catabolism, and elimination10.

Enzymes involved in lipoprotein metabolism

Lipoprotein lipase (LPL)

LPL is a multifunctional enzyme expressed on endothelial cells in the heart, muscle, adipose tissue, macrophages and lactating mammary glands. LPL plays a critical function in the hydrolysis of triglyceride (TG) into 2 costless fatty acids and monoacylglycerol. Also LPL helps in the receptor-mediated lipoprotein uptake of chylomicron remnants, cholesterol-rich lipoproteins, and free fatty acids11.

Hepatic lipase (HL)

HL is a multifunctional poly peptide that regulate lipoprotein metabolism. It is synthesized by hepatocytes andfound in adrenalgland and ovary. HL hydrolyzes phospholipids and triglycerides of plasmalipoproteins. In addition HL affects cellular lipid delivery by facilitating lipoprotein absorption past prison cell surface receptors and proteoglycans12.

Lecithin cholesterol acyl transferase (LCAT)

Lecithin cholesterol acyltransferase,is a crucial enzyme in the metabolism of HDL. It converts costless cholesterol into cholesteryl esters which then sequestered into the core of lipoprotein andfinally making mature HDL13.

Cholesteryl ester transfer protein (CETP)

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer poly peptide, is a hydrophobic plasma glycoprotein that accelerates the transferring of esterified cholesterol esters (CE) from HDLs to chylomicrons, VLDL and LDL, in exchange for triglyceride. ACETP deficiency is linked to increased HDL levels and decreased LDL levelsxiv.

Microsomal triglyceride protein (MTP)

Microsomal triglycerideprotein (MTP) is a lipid transfer protein catalyzesthe transfer of neutral lipids, triglycerides and cholesterol esters between membrane of the lumen of microsomes isolated from the liver and intestinal mucosa.Microsomal triglycerideprotein is an essential protein in the assembly of apo B containing lipoproteins.Now it is known that MTP is important in the biosynthesis of glycolipid presenting moleculesand the regulation of cholesterol ester biosynthesis15

Acyl Co-A transferase (ACAT)

Acyl Co-A transferase (ACAT) is membrane-bound poly peptide that useslong-chain fat acyl-CoA and cholesterol as substrates to produce cholesteryl esters. ACAT playssignificant roles in cellular cholesterol homeostasis in various tissues and prevents the toxic accumulation of excess cholesterol in a cell. Furthermore,the importance of ACAT arises from its crucial office inthe associates forth withthe secretion of apolipoprotein-B containing lipoproteins in the liver and intestinessixteen.

Lipid metabolism

About all the dietary fats are absorbed from the intestinal lumen into the intestinal lymph and packed into chylomicrons. These lipoproteins move into the claret stream where they got hydrolyzed past endothelial lipoprotein lipasewhich hydrolyzes the triglycerideinto glycerol and non-esterified fatty acids. Afterwards which the chylomicron remnants are absorbed in the liver and packaged withcholesterol,cholesteryl esters and ApoB100 to form VLDL. Subsequently the release of VLDL into the blood stream information technology volition exist converted into IDL by the action of lipoprotein lipase and hepatic lipase,where phospholipids and apolipoproteins transferred back to HDL. Furthermore, after the hydrolysis by hepatic lipase, IDL will exist converted to LDLand loss more than apolipoproteins17.

Peripheral cholesterol is returned to the liver by reverse cholesterol transport pathway using HDLs which are originally synthesized past the liver and released into the claret. In the claret, HDL cholesterol is esterified past LCAT to cholesteryl ester and transferred to VLDL and chylomicrons to return to the liver through LDL receptor. Cholesteryl ester are transferred to LDL particles by CETP and so subjected to LDL-receptors mediated endocytosis. Finally, cholesteryl esters are hydrolyzed to cholesterol and extracted from the torso every bit bile acid18

Hyperlipidemia classification

Hyperlipidemiain general can be classified to:

Primary

it is besides called familial due to a geneticdefect, it may exist monogenic: a single gene defect or polygenic: multiple gene defects.Primary hyperlipidemia can usually exist resolved intoone of the abnormal lipoprotein patternssummarized in tabular array one19.

Secondary

it is caused because it is caused by some other disorder similar diabetes, nephritic syndrome, chronic alcoholism, hypothyroidism and with utilize of drugs like corticosteroids, beta blockers and oral contraceptives. Secondary hyperlipidemia together with significanthypertriglyceridemiacan cause pancreatitistwenty.

The primary cause of hyperlipidemia includes changes in lifestyle habits in which gamble gene is mainly poor diet in which fat intakeform saturated fat and cholesterol exceeds 40 percent of the total calories uptake20.

Table 1: Fredrickson classification of primary hyperlipidemia19.

Type

Disorder

Cause

Occurrence

Elevated plasma lipoprotein

I

 

Familial hyperchylomicronemia

Or

Primary hyperlipoproteinemia

  

Lipoprotein lipase deficiency

or

Altered ApoC2

  

Very rare

  

Chylomicrons

IIa

 

Familial hypercholesterolemia

Or

Polygenic hypercholesterolemia

  

LDL receptor deficiency

  

Less common

  

LDL

IIb

 

Familial combined hyperlipidemia

 Decreased LDL receptor and increased ApoB  

Commonest

  

LDL and VLDL

III

Familial dysbetalipoprotenemia  

Defect in Apo E- 2 synthesis

  

Rare

  

IDL

Iv

 

Familial hypertriglyceridemia

  

Increased VLDL product and decreased excretion

  

mutual

  

LDL

V

 

Endogenous hypertriglyceridemia

  

Increased VLDL production and decreased LPL

  

Less mutual

  

VLDL and chylomicrons

Symptoms of hyperlipidemia

Generally hyperlipidemia does not have whatsoever obvious symptoms only they are usually discovered during routine examination or until it reaches the danger phase of a stroke or eye assault. Patients with loftier claret cholesterol level or patients with the familial forms of the disorder can develop xanthomaswhich are deposits of cholesterol may form under the peel, especially under the optics.At the same time, patients with elevated levels of triglycerides may develop numerous pimple-like lesions at different sites in their body19.

Complications of hyperlipidemia

Atherosclerosis

Hyperlipidemia is the most of import risk factor for atherosclerosis, which is the major crusade of cardiovascular disease.Atherosclerosisis a pathologic processcharacterized past the accumulation of lipids, cholesterol and calciumand the development of fibrous plaques within the walls of large and medium arteries21.

Coronary Artery Affliction (CAD)

Atherosclerosis, the major cause of coronary artery disease, characterized by the aggregating of lipid and the formation of gristly plaqueswithin the wall of the arteries resulting in narrowing of the the arteries that supply blood to the myocardium, and results in limiting blood menses and insufficient amounts of oxygen to run across the needs of the heart. Elevated lipid profilehas been connected to the development of coronary atherosclerosis22.

Myocardial Infarction (MI)

MI is a condition which occurs when blood and oxygen supplies are partially or completely blocked from flowing in one or more cardiac arteries, resulting in damage or decease of heart cells. The occlusion may exist due to ruptured atherosclerotic plaque. The studies show thatabout 1-quaternary of survivors of myocardial infarctionwere hyperlipidemic23.

Ischemic stroke

stroke is the fourth leading cause of expiry. Usually strokes occur due to blockage of an artery by a blood clot or a slice of atherosclerotic plaque that breaks loose in a pocket-sized vessel within the encephalon.Many clinical trials revealed thatlowering of low-density lipoprotein and total cholesterol past fifteen% significantly reduced the risk of the offset stroke24.

Drugs classes for hyperlipidemia

Since LDL is the major atherogeniclipoprotein, reduction of this lipoprotein would be expected to reduceatherosclerosis and therefore reducecardiovascular agin effects. In addition to high LDL,presence of risk factors and CHD should qualify initiating drug therapy along with life style irresolute. Monotherapy has been shown to be effective in treating hyperlipidemia, but combination therapy may be required for a comprehensive arroyo. Currently, antihyperlipidemic drugs comprise five major classes (Table 2) that include statins, fibric acid derivatives, bile acid binding resins, nicotinic acid derivatives and drugs that inhibit cholesterol absorptiontwenty.

Table 2: Drug therapy for hyperlipidemia20.

Drugs

Effects on lipids

 

Statins:

Lovastatin   (10-80 mg)

Simvastatin  (5-40 mg)

Atorvastatin    (10-80 mg)

Rosuvastatin  (5- 20 mg)

  

Subtract TG

Subtract LDL

Increase HDL
 

Bile acid binding resins:

Cholestyramine  (4-16 mg)

Colestipol(five-30 mg)

  

TG  generally noteffected

Decrease LDL

Increment HDL
 

Fibric acid derivatives:

Gemfibrozil (1200 mg)

Bezafibrate  (600 )mg

Fenofibrate(200 mg)

  

Decrease TG

Decrease LDL

Increase HDL
 

Nicotinic acid derivatives

Niacin(2-half dozen gm)

  

Decrease TG

Subtract LDL

Increase HDL
 

Cholesterol absorption inhibitors:

Ezetimibe ( 10 mg )

  

Decrease LDL

Subtract cholesterol

iii-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductaseinhibitors (statins).

This class includes (Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin and Rosuvastatin). Statinsare broadly prescribed in the treatment of hypercholesterolemia, can achieve 20%–fifty% reductions in cholesterol levels and have been linked to the reduced incidence of coronary morbidity and mortality in loftier-gamble adults25.

Mechanism of action

Thesedrugs are structural analogues of HMG-coenzyme Areductase. They act past inhibiting the rate limiting enzyme (HMG-coenzyme Areductase) in the biosynthesis of cholesterol in the liver. By inhibiting this enzyme, statins significantly reduce plasma levels of full cholesterol (TC),LDL and ApoB. Meanwhile, statins also cause a pocket-size subtract in plasma triglycerides and a pocket-sized increment in plasma level of HDL26.

Other HMG-CoA reductase inhibitors includethe diallyldisulfide (DADS) anddiallylthiosulfinate. DADS, is an organosulfur chemical compound derived from garlic, has been shown to reduce cholesterol synthesisby 10–25% at low concentrations. Diallylthiosulfinate,a metabolite of allicin, block the formation of 7-dehydrocholesteroland reduced the production of cholesterol. Bis-(3-(4-nitrophenyl)prop-2-ene)disulfide, a new derivatives of diallyldisulfide,is constructive in reducing plasma total cholesterol27.

Side furnishings

Statins are oftentimes well toleratedwith the almost mutual adverse effectsbeing transient gastrointestinal symptoms,headache, myalgia and dizziness.These symptoms are more commonwith college doses and may solve ifa unlike statin is used28.

Statins as well cause myopathy, rhabdomyolsisand an increase serum transaminase. These substances are harmful to the kidney and often cause kidney damage. Additionally statins may crusade cardiomyopathy29. Recent clinical trials showed that statin utilize has been linked to anincrease in type 2 diabetes30.

Bile acrid sequestrants

Bile acid synthesis is the main pathway of cholesterolcatabolism in the liver; information technology has been estimated that about 500 mg of cholesterolis converted daily into bile acids in the adult humanliver.Bile acidsare secreted into the intestine and take an important role in facilitating the assimilation of fats from food31.

Bile acid sequestrantsincludecholestyramine, colestipol, colestimide,and colesevelam. Cholestyramineand colestipol are the two bile acrid sequestrants currently available.Cholestyramineis a 4th amine composed of styrene and divinylbenzenepolymers. Colestipolis a copolymer of diethylenetriamine and one-chloro-2,3-epoxypropane32.

Mechanism of action

Bile acid sequestrants are positively charged resins that demark to the negatively charged bile acids in the intestine to form a large insoluble circuitous that not absorbed and then excreted in the feces. Excretion is increased up to tenfold when resins are given, resulting in greater conversion of cholesterol to bile acids. Furthermore bile acid sequestrants increment HDL levels33.

Side effects

Bile acid sequestrants are rarely used equally initial therapy because of poor patient tolerance. Gastrointestinal disturbances are the most mutual complaints of the bile acid sequestrantsinclude constipation, nausea, indigestion,bloating and flatulence34.

On long-term therapybile acid sequestering agents may cause osteoporosis due to calcium loss.They may aggravatehypertriglyceridemia by an unknownmechanism.Some vitamins minerals deficiencymay occur32.

Fibric acid derivatives(Fibrates)

Fibratesinclude clofibrate,gemfibrozil,fenofibrate, andbezafibrate, areawidely used class of antihyperlipidemicagents, results in a significantreduction in plasmatriglycerides and a modestreduction in LDL cholesterol. HDL cholesterol level increases moderately. Angiographictrials results showed that fibrates play an important role in slowing the progression of coronaryatherosclerosis and decrease the incidence of coronary avenue affliction.

Mechanism of action

Data from studies in rodents and in humans imply fourmainmechanisms of fibrates:

Stimulation of lipoprotein lipolysis.

Fibrates role primarily as ligands for the nuclear transcription receptor, PPAR-α. They increased the expression of lipoprotein lipase, apo, and down-regulate apo C-III, an inhibitor of lipolysis. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI andapo AII35.

Increase hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production.

Fibrates raise the product of fatty acid transport protein and acyl-CoA synthetase, which contribute to the increase uptake of fatty acid by the liver and as a result in a lower availability of fat acids for triglyceride product36.

Increase removal of LDL particles.

Fibrate, appears to enhance LDL catabolism via the receptor-mediated pathway; LDL particles became larger and more lipid rich and therefore had more than affinity for receptors.Fibrates as well inhibits the germination of slowly metabolized, potentially atherogenic LDL particles37.

Increase in HDL product and stimulation of reverse cholesterol transport.

Fibrates increase apo A-I production in the liver which leads to the observed summit in plasma levels of apo A4 and HDL-cholesteroland a more effective opposite cholesterol ship38.

Side furnishings

Generally, fibrates are considered to be well tolerated. Side effects may includegastrointestinalsymptoms, myopathy, arrhythmia, peel rashes and gallstones.Fibrates should be avoided in patients with liver and renal dysfunction32.

Nicotinic acid derivatives (Niacin)

Niacin,a water-soluble vitamin of blazon B, is the oldest lipid lowering agent used totreat hyperlipidemia and proved to decrease cardiovascular morbidity and total mortality. Information technology decreases total cholesterol, LDL cholesterol, triglycerides.

Likewise, niacin is the near constructive therapy available for the treatment of low HDL levels when used in a dose of (≈1 gm per solar day)39.

Mechanism of action

Niacin inhibits hormone-sensitive lipase which decreases triglycerides lipolysis the main producer of circulating gratis fatty acids. The liver usually uses these circulating fatty acids equally a major precursor for triacylglycerol synthesis. Therefore, niacin inhibits VLDL secretion, in plough decreasing production of LDL.

Furthermore, niacintreatment elevates HDL cholesterol concentrationsby reducing the fractional clearance of apo A-1 and increasing HDL synthesis32.

Side effects

Niacin treatment has been plagued past low compliance rates. The most mutual side effects areintense cutaneous flush which bear on more than than iii quarters of patients, itching, headache andsome patients experience nausea and intestinal discomfort. Niacin also elevates liver enzymes.

Administering statins in combination with niacin increases the incidence ofrhabdomyolysis.Niacin as well promotes glucose in tolerance and hyperuricemia which precipitate a gout attack34.

Selective cholesterol absorption inhibitor (Ezetimibe)

The discovery and development of ezetimibe, the first member of a grouping of drugs that inhibit intestinal absorption of phytosterols and cholesterol, has improved the treatment of hypercholesterolemia.It inhibits the absorption of cholesterol from the pocket-size intestine without any outcome on the plasma concentrations of the fat-soluble vitaminstwoscore.

A combination of statins and ezetimibe can achieve a reduction in LDL cholesterol levels by25%, compared to 6% attained past doubling the statin dose41.

Mechanism of action

Ezetimibeselectively inhibits assimilation of cholesterol in the smallintestine, leading to a subtract in the delivery of abdominal cholesterol to the liver past blocking the Niemann–Pick C1-like 1 protein (NPC1L1), a human sterol transport protein. This causes an increase in the clearance of cholesterol from the blood42.

Side effects

Ezetimibeis usually well tolerated; the nigh common side effects include headache, abdominalpain and diarrhea. Ezetimibe appears to cause elevations in liver function tests include elevations in alanine transaminase and aspartate transaminase43.

New potential targets and treatments

Recently, many clinical trials revealed new potential agents with promisingantihyperlipidemic action. In this section, some of these agents will be reviewed.

Acyl-CoA cholesterol acyl transferase inhibitors(ACAT)

Acyl-CoA cholesterol acyl transferase (ACAT) is the enzyme that catalyzes the conversion of intracellular cholesterol into cholesteryl esters. ACAT has two isomers, termed ACAT1 and ACAT2.

ACAT1 contributes to cream cell formation in the arterial wall and the evolution of atherosclerosis, and so ACAT-1 inhibitors may haveantiatherogenic effect and ACAT-2 inhibitors mayplay an of import part in reducing cholesterol absorption in the intestine.

AvasimibeandEflucimibe deed by inhibiting ACAT, decrease plasma cholesterol levels and deadening the development of atherosclerosis44,45. Some of the potent ACAT inhibitorswhichare currentlyin clinical developmentare naphthoquinone derivatives46.

Microsomal triglyceride transfer protein (MTP) inhibitors

Microsomal triglyceride transfer protein (MTP) has multiple functions including transferring neutral lipids betwixt membrane vesicles, the biosynthesis of CD1, antigen-presenting molecules, also as in the regulation of cholesterol ester biosynthesis. Therefore, inhibiting MTP causessignificant reductions in plasma triglycerides, LDL, and VLDL cholesterol. These findings suggest that inhibitors of MTP might exist useful for reducing the atherogenic lipoproteinslevelsfifteen.

A series of newly synthesized phosphonate esters were evaluated for their effects on MTP activity andthey exhibita potent inhibition bothin vitro and in vivo. Data also advise the potency oflomitapide (AEGR-733, formerly BMS-201038), a novel drug for hypercholesterolemia47.

Cholesteryl ester transfer protein (CETP) inhibitors

CETP in liverfacilitates the transfer of cholesteryl esters from anti-atherogenic HDLs to proatherogenicapolipoprotein B containing lipoproteins, including VLDLs and LDLs. Furthermore, most studies showed that there is evidence that CETP may playa proatherogenic part by involving in reverse cholesteroltransport and back up the idea that inhibition of CETP slows the progression of atherosclerosis48.

Dalcetrapib and anacetrapib are novel compounds in Phase 3 of clinical trials. Dalcetrapib reduced CETP activity by fifty% andelevated HDL cholesterol levels by 31% without affecting LDL cholesterol levels49.

Squalene synthase inhibitors

Squalene synthase (SqS) catalyzes farnesyl pyrophosphate to course squalene, Catalysis past SqS is the commencement committed pace in sterol synthesis, and ane of these sterols is cholesterol.Pharmacologists regard SqS inhibitors as promising lead compounds in the evolution of potential agents to care for hyperlipoproteinemial.

It has been reported that subsequently oral administration ofBMS-188,494,a potential inhibitor of SqS,the plasma levels of cholesterol was reduced in experimental rats51. Meantime, YM-53601,another inhibitor of SqS,reduces plasma cholesterol and triglyceride levels52.

Hydroxymethylglutaryl-CoA synthase  inhibitors

HMG synthase catalyzes the chemic reaction that converts acetyl-CoA and acetoacetyl-CoA to iii-hydroxy-3-methylglutaryl-CoA. 50-659,699 is 1 of the compounds that have shown a potentialHMG synthase inhibitor activity52.

ATP citrate lyase inhibitors

ATP citrate lyase (ACL)is the primary enzyme answerable for the synthesis of cytosolicacetyl-CoAand oxaloacetate. Synthesis of cytosolicacetyl-CoA and oxaloacetate stand for animportant footstep in the synthesis of fatty acids and cholesterol. For this reason, inhibition of ACL is a promising strategy in the treatmentof dyslipidemia53.

Recently, Li et al. described that a chronic assistants of BMS-303141, the leading inhibitor of the enzyme ACL in the2-hydroxy-Northward-arylbenzenesulfonamides grade, in loftier-fatty–fed mice reduced weight proceeds and decreased plasma cholesterol, triglycerides, and glucose54.

Acyl coenzyme A: diacyl glycerol acyltransferase (DGAT )

DGAT is a microsomal enzyme that joins Acyl CoAto 1,ii-diacylglycerol in the finalstep in triglyceride biosynthesis. Two forms ofDGAT(DGAT-one and 2) have been identified.Several studies showed that inhibition of DGAT1 is a practiced target in the treatment of hyperlipidemia.

The chemical compound T863 is a potent inhibitor for DGAT1 in vitro; it was shown that a two weeks treatment with compound T863 decreased serum and liver triglycerides, and decreased serum cholesterolin mice55.

Squaleneepoxidase inhibitors

Squaleneepoxidaseis one of the charge per unit-limiting enzymes for the offset oxygenation step in sterol biosynthesis. NB-598 competitivelyinhibits squaleneepoxidase andinhibits cholesterol synthesis56.

Lanosterol synthase inhibitors

lanosterol synthase (LSS)Catalyzes the cyclization of (S)-2,iii oxidosqualene to lanosterol, the initial sterol intermediate in thecholesterol synthesis pathway.LSS inhibitors such equally U18666A and Ro 48-8071 have a potential to decrease plasmaLDL cholesterol levels57.

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