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

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

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.

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 risk factors causingcardiovascular diseases (CVDs).CVDs accounts for one third of total deaths around the world, it is believed that CVDs will turn out to be the main cause of death and disability worldwide by the year 20201,2.

Hyperlipidemia isan increasein one or more 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 levels3,4.

Hypercholesterolemia and hypertriglyceridemia are the main causeof atherosclerosis which is strongly related to ischemic heart disease (IHD)5. There is a strong relation between IHD and the high mortality rate. Furthermoreelevated plasma cholesterol levels cause 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 lead to oxidative modifications in low-density lipoproteins, which present a significant function inthe initiation and progression of atherosclerosis and associated cardiovascular diseases3.

Plasma lipoproteins

Composition and structure

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

Lipoproteinscomposed from non-polarlipids(triglycerides and cholesteryl esters),polar lipids(phospholipids and unesterified cholesterol)and specific proteinsknown as 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 five classes of lipoproteins present in plasma.Theseclasses areheterogeneous;they have different composition, size, and density8.

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 order to transporttriglycerides, an importantenergy source,which synthesized and absorbedto places of utilization and storage;and to transport cholesterol between different 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 role in the hydrolysis of triglyceride (TG) into two free fatty acids and monoacylglycerol. Besides 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 protein 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 by cell surface receptors and proteoglycans12.

Lecithin cholesterol acyl transferase (LCAT)

Lecithin cholesterol acyltransferase,is a crucial enzyme in the metabolism of HDL. It converts free 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 protein, 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 levels14.

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 protein that useslong-chain fatty 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 role inthe assembly along withthe secretion of apolipoprotein-B containing lipoproteins in the liver and intestines16.

Lipid metabolism

Almost all the dietary fats are absorbed from the intestinal lumen into the intestinal lymph and packed into chylomicrons. These lipoproteins move into the blood stream where they got hydrolyzed by endothelial lipoprotein lipasewhich hydrolyzes the triglycerideinto glycerol and non-esterified fatty acids. After which the chylomicron remnants are absorbed in the liver and packaged withcholesterol,cholesteryl esters and ApoB100 to form VLDL. After the release of VLDL into the blood stream it will be 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 be converted to LDLand loss more apolipoproteins17.

Peripheral cholesterol is returned to the liver by reverse cholesterol transport pathway using HDLs which are originally synthesized by the liver and released into the blood. In the blood, HDL cholesterol is esterified by 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 then subjected to LDL-receptors mediated endocytosis. Finally, cholesteryl esters are hydrolyzed to cholesterol and extracted from the body as bile acid18

Hyperlipidemia classification

Hyperlipidemiain general can be classified to:

Primary

it is also called familial due to a geneticdefect, it may be monogenic: a single gene defect or polygenic: multiple gene defects.Primary hyperlipidemia can usually be resolved intoone of the abnormal lipoprotein patternssummarized in table 119.

Secondary

it is acquired because it is caused by another disorder like diabetes, nephritic syndrome, chronic alcoholism, hypothyroidism and with use of drugs like corticosteroids, beta blockers and oral contraceptives. Secondary hyperlipidemia together with significanthypertriglyceridemiacan cause pancreatitis20.

The main cause of hyperlipidemia includes changes in lifestyle habits in which risk factor 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 production and decreased excretion

 

common

 

LDL

 

V

 

Endogenous hypertriglyceridemia

 

Increased VLDL production and decreased LPL

 

Less common

 

VLDL and chylomicrons

 

Symptoms of hyperlipidemia

Generally hyperlipidemia does not have any obvious symptoms but they are usually discovered during routine examination or until it reaches the danger stage of a stroke or heart attack. Patients with high blood cholesterol level or patients with the familial forms of the disorder can develop xanthomaswhich are deposits of cholesterol may form under the skin, especially under the eyes.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 important risk factor for atherosclerosis, which is the major cause of cardiovascular disease.Atherosclerosisis a pathologic processcharacterized by the accumulation of lipids, cholesterol and calciumand the development of fibrous plaques within the walls of large and medium arteries21.

Coronary Artery Disease (CAD)

Atherosclerosis, the major cause of coronary artery disease, characterized by the accumulation of lipid and the formation of fibrous plaqueswithin the wall of the arteries resulting in narrowing of the the arteries that supply blood to the myocardium, and results in limiting blood flow and insufficient amounts of oxygen to meet 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 death of heart cells. The occlusion may be due to ruptured atherosclerotic plaque. The studies show thatabout one-fourth of survivors of myocardial infarctionwere hyperlipidemic23.

Ischemic stroke

stroke is the fourth leading cause of death. Usually strokes occur due to blockage of an artery by a blood clot or a piece of atherosclerotic plaque that breaks loose in a small vessel within the brain.Many clinical trials revealed thatlowering of low-density lipoprotein and total cholesterol by 15% significantly reduced the risk of the first stroke24.

Drugs classes for hyperlipidemia

Since LDL is the major atherogeniclipoprotein, reduction of this lipoprotein would be expected to reduceatherosclerosis and therefore reducecardiovascular adverse effects. In addition to high LDL,presence of risk factors and CHD should qualify initiating drug therapy along with life style changing. Monotherapy has been shown to be effective in treating hyperlipidemia, but combination therapy may be required for a comprehensive approach. Currently, antihyperlipidemic drugs contain five major classes (Table 2) that include statins, fibric acid derivatives, bile acid binding resins, nicotinic acid derivatives and drugs that inhibit cholesterol absorption20.

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)

 

 

Decrease TG

Decrease LDL

Increase HDL

 

Bile acid binding resins:

Cholestyramine  (4-16 mg)

Colestipol(5-30 mg)

 

 

TG  generally noteffected

Decrease LDL

Increase HDL

 

Fibric acid derivatives:

Gemfibrozil (1200 mg)

Bezafibrate  (600 )mg

Fenofibrate(200 mg)

 

 

Decrease TG

Decrease LDL

Increase HDL

 

Nicotinic acid derivatives

Niacin(2-6 gm)

 

 

Decrease TG

Decrease LDL

Increase HDL

 

Cholesterol absorption inhibitors:

Ezetimibe ( 10 mg )

 

 

Decrease LDL

Decrease cholesterol

 

3-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%–50% reductions in cholesterol levels and have been linked to the reduced incidence of coronary morbidity and mortality in high-risk adults25.

Mechanism of action

Thesedrugs are structural analogues of HMG-coenzyme Areductase. They act by 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 total cholesterol (TC),LDL and ApoB. Meanwhile, statins also cause a modest decrease in plasma triglycerides and a small increase in plasma level of HDL26.

Other HMG-CoA reductase inhibitors includethe diallyldisulfide (DADS) anddiallylthiosulfinate. DADS, is an organosulfur 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 effective in reducing plasma total cholesterol27. 

Side effects

Statins are frequently well toleratedwith the most common adverse effectsbeing transient gastrointestinal symptoms,headache, myalgia and dizziness.These symptoms are more commonwith higher doses and may solve ifa different statin is used28.

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

Bile acid sequestrants

Bile acid synthesis is the main pathway of cholesterolcatabolism in the liver; it 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 have an important role in facilitating the absorption of fats from food31.

Bile acid sequestrantsincludecholestyramine, colestipol, colestimide,and colesevelam. Cholestyramineand colestipol are the two bile acid sequestrants currently available.Cholestyramineis a quaternary amine composed of styrene and divinylbenzenepolymers. Colestipolis a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane32.

Mechanism of action

Bile acid sequestrants are positively charged resins that bind to the negatively charged bile acids in the intestine to form a large insoluble complex that not absorbed and so 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 increase HDL levels33.

Side effects

Bile acid sequestrants are rarely used as initial therapy because of poor patient tolerance. Gastrointestinal disturbances are the most common 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 artery disease.

Mechanism of action

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

Stimulation of lipoprotein lipolysis.

Fibrates function 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 enhance the production 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 fatty acids for triglyceride production36.

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 affinity for receptors.Fibrates also inhibits the formation of slowly metabolized, potentially atherogenic LDL particles37.

Increase in HDL production and stimulation of reverse cholesterol transport.

Fibrates increase apo A-I production in the liver which leads to the observed elevation in plasma levels of apo A4 and HDL-cholesteroland a more effective reverse cholesterol transport38.

Side effects

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

Nicotinic acid derivatives (Niacin)

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

Besides, niacin is the most effective therapy available for the treatment of low HDL levels when used in a dose of (≈1 gm per day)39.

Mechanism of action

Niacin inhibits hormone-sensitive lipase which decreases triglycerides lipolysis the main producer of circulating free fatty acids. The liver usually uses these circulating fatty acids as a major precursor for triacylglycerol synthesis. Therefore, niacin inhibits VLDL secretion, in turn 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 by low compliance rates. The most common side effects areintense cutaneous flush which affect more than three quarters of patients, itching, headache andsome patients experience nausea and abdominal discomfort. Niacin also elevates liver enzymes.

Administering statins in combination with niacin increases the incidence ofrhabdomyolysis.Niacin also 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 group of drugs that inhibit intestinal absorption of phytosterols and cholesterol, has improved the treatment of hypercholesterolemia.It inhibits the absorption of cholesterol from the small intestine without any effect on the plasma concentrations of the fat-soluble vitamins40.

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

Mechanism of action

Ezetimibeselectively inhibits absorption of cholesterol in the smallintestine, leading to a decrease in the delivery of intestinal cholesterol to the liver by 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 most 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 activity. 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 foam cell formation in the arterial wall and the development of atherosclerosis, so ACAT-1 inhibitors may haveantiatherogenic effect and ACAT-2 inhibitors mayplay an important role in reducing cholesterol absorption in the intestine.

AvasimibeandEflucimibe act by inhibiting ACAT, decrease plasma cholesterol levels and slow 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 between membrane vesicles, the biosynthesis of CD1, antigen-presenting molecules, as well 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 be useful for reducing the atherogenic lipoproteinslevels15.

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 suggest 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 role by involving in reverse cholesteroltransport and support the idea that inhibition of CETP slows the progression of atherosclerosis48.

Dalcetrapib and anacetrapib are novel compounds in Phase III of clinical trials. Dalcetrapib reduced CETP activity by 50% andelevated HDL cholesterol levels by 31% without affecting LDL cholesterol levels49.

Squalene synthase inhibitors

Squalene synthase (SqS) catalyzes farnesyl pyrophosphate to form squalene, Catalysis by SqS is the first committed step in sterol synthesis, and one of these sterols is cholesterol.Pharmacologists regard SqS inhibitors as promising lead compounds in the development of potential agents to treat hyperlipoproteinemia50.

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

Hydroxymethylglutaryl-CoA synthase  inhibitors

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

ATP citrate lyase inhibitors

ATP citrate lyase (ACL)is the primary enzyme accountable for the synthesis of cytosolicacetyl-CoAand oxaloacetate. Synthesis of cytosolicacetyl-CoA and oxaloacetate represent animportant step 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 administration of BMS-303141, the leading inhibitor of the enzyme ACL in the2-hydroxy-N-arylbenzenesulfonamides class, in high-fat–fed mice reduced weight gain and decreased plasma cholesterol, triglycerides, and glucose54.

Acyl coenzyme A: diacyl glycerol acyltransferase (DGAT)

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

The 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 rate-limiting enzymes for the first oxygenation step in sterol biosynthesis. NB-598 competitivelyinhibits squaleneepoxidase andinhibits cholesterol synthesis56.

Lanosterol synthase inhibitors

lanosterol synthase (LSS)Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, the initial sterol intermediate in thecholesterol synthesis pathway.LSS inhibitors such as U18666A and Ro 48-8071 have a potential to decrease plasmaLDL cholesterol levels57.

References

  1. Ginghina, C., Bejan, I.,Ceck, C. D. Modern risk stratification in coronary heart disease.J. Med. Life., 2011; 4(4): 377-86.
  2. Jorgensen, T., Capewell, S., Prescott, E., Allender, S., Sans, S.,Zdrojewski, T. Population-level changes to promote cardiovascular health. Eur. J. Prev. Cardiol., 2013; 20(3):409-21.
  3. Mishra, P. R., Panda, P. K., Apanna, K.C., Panigrahi, S. Evaluation of acute hypolipidemic activity of different plant extracts in Triton WR-1339 induced hyperlipidemia in albino rats. Pharmacologyonline.,2011;3: 925-934.
  4. Jeyabalan, S., Palayan, M. Antihyperlipidemic activity of Sapindusemarginatus in Triton WR-1339 induced albino rats.Res. J. Pharm. Tech., 2009; 2(2):319-323.
  5. Brouwers, M. C.,VanGreevenbroek, M. M.,Stehouwer, C. D.,de Graaf, J.,Stalenhoef, A. F. Thegenetics of familial combined hyperlipidaemia.Nat. Rev. Endocrinol.,2012; 8(6): 352-62.
  6. Kumar, D., Parcha, V.,Maithani, A., Dhulia, I. Effect and evaluation of antihyperlipidemic activity guided isolated fraction from total methanol extract of Bauhinia variegata (linn.) in Triton WR–1339 induced hyperlipidemic rats.Asian Pac. J. Trop. Dis.,2012;2(2): 909-913.
  7. Wells, G. B.,Dipiro, J., Schwinghammer, T., Hamilton, C. Phamacotherapy Handbook, 7thedn, USA, TheMcgraw Hill Companies, 2007; pp98-108.
  8. Scapa, E. F.,Kanno, K., Cohen, D.E. Lipoprotein metabolism In: Rodés,J.; Benhamou, J. P.; Blei, A. T.; JürgReichen, J. and Mario Rizzetto, M.,Hepatology: From Basic Science to Clinical Practice, 3rdedn, U.K: Blackwell Publishing Ltd, 2007; pp133-134.
  9. Jonas, A. Lipoprotein structure In: (Vance DE, Vance JE), Biochemistry of Lipids, Lipoproteins and Membranes, 4thedn, Amsterdam: Elsevier, 2002; pp483–504.
  10. Harvey, R. A., Ferrier, D. R. Cholesterol and steroid metabolism In: (Rhyner, S.), Biochemistry, 5th edn, USA: Lippincott Williams & Wilkins, 2011; pp227-237.
  11. Wang, H.,Eckel, R. H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol.Endocrinol.Metab.,2009; 297 (2): 271-288.
  12. Santamarina-Fojo, S.,González-Navarro, H., Freeman, L., Wagner, E.,Nong, Z. Hepatic lipase, lipoprotein metabolism, and atherogenesis.Arterioscler.Thromb.Vasc.Biol.,2004; 24(10): 1750-1754.
  13. Nakhjavani, M., Morteza, A.,Karimi, R.,Banihashmi, Z.,Esteghamati, A. Diabetes induces gender gap on LCAT levels and activity.life Sci., 2013; 92(1): 51–54.
  14. Durrington, P. N. Cholesteryl ester transfer protein (CETP) inhibitors. Br. J. Cardiolo.,2012; 19(3):126–133.
  15. Hussain, M., Rava, P., Walsh, M., Rana, M., Jahangir Iqbal, J. Multiple functions of microsomal triglyceride transfer protein.Nutr.Metab.,2012; (9):14-30.
  16. Chang, T. Y., Li, B. L., Chang, C. Y., Urano, Y. Acyl-coenzyme A: cholesterol acyltransferases.Am. J. Physiol- Endoc. M.,2009; 297(1): E1-E9.
  17. McLaren J. E., Michael D. R., Ashlin T. G., Ramji D. P.Cytokines, macrophage lipid metabolism and foam cells: Implications for cardiovascular disease therapy.Prog. Lipid Res.,2011; 50(4):331–347.
  18. Hegele, A. R. Plasma lipoproteins: genetic influences and clinical implications.Nat. Rev. Genet.,2009; (10): 109-121.
  19. Tripathi, K. D. Essentials of Medical Pharmacology, 6thedn, India: JP brothers medical publishers, 2008; pp613-614.
  20. Joseph, D. Pharmacotherapy, A pathophysiological approach, 8thedn, The McGraw Hill companies, Inc. 2011; pp370.
  21. Wouters, K., Shiri-Sverdlov, R., van Gorp, P. J., van Bilsen, M., Hofker, M.H. Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice.Clin. Chem. Lab. Med., 2005; 43(5):470-9.
  22. Gao, W.,He, H. W, Wang, Z. M., Zhao, H., Xiao-Qing Lian, X. Q., Wang, Y. S., Zhu, J., Jian-Jun Yan, J. J., Zhang, D. G., Zhi-Jian Yang, Z. J., Wang, L. S. Plasma levels of lipometabolism-related miR-122 and miR-370 are increased in patients with hyperlipidemia and associated with coronary artery disease.Lipids Health Dis.,2012; (11): 55.
  23. Nickolas, T.L.,Radhakrishnan, J.,Appel, G.B. Hyperlipidemia and thrombotic complications in patients with membranous nephropathy.Semin.Nephrol.; 2003; 23(4):406-11.
  24. Amarenco, P., Labreuche, J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol., 2009; 8 (5): 453 – 463.
  25. Belay, B.,Belamarich, P. F., Tom-Revzon, C. The use of statins in pediatrics: knowledge base, limitations, and future directions. Pediatrics.,2006; 119(2): 370–380.
  26. Eiland, L. S.,Luttrell, P. L. Use of statins for dyslipidemia in the pediatric population.J. Pediatr. Pharmacol. Therap.,2010; 15(3): 160–172.
  27. Sharma, M.,Tiwari, M., Chandra, R. Bis[3-(4′-substituted phenyl)prop-2-ene]disulfides as a new class of antihyperlipidemic compounds.Bioorg. Med. Chem. Lett., 2004; 14(21); 5347-5350.
  28. Mahley, R. W., Bersot, T. P. Drug therapy for hypercholesterolemia and dyslipidemia, In: Hardman, J.G.; Limbird, L. E. and Gilman, A. G., Goodman & Gilman’s, The Pharmacological Basis of Therapeutics. 10thedn, New York: McGraw Hill, 2001; pp971–1002.
  29. Bellosta, S.,Paoletti, R.,Corsini, A. Atherosclerosis: Evolving vascular biology and clinical implications, safety of statins: focus on clinical pharmacokinetics and drug interactions.Circulation.,2004; (109): 50-57.
  30. Mills, E. J.,Wu, P.,Chong, G.,Ghement, I.,Singh, S.,Akl. E. A.,Eyawo, O.,Guyatt, G.,Berwanger, O., Briel, M. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials.QJM.,2011; 104(2):109-124.
  31. Russell, D. W. The enzymes, regulation, and genetics of bile acid synthesis, Annu. Rev. Bioch.,2003; (72): 137–174.
  32. Kishor, S., Kathiravan, M., Somani, R., Shishoo, C.H. The biology and chemistry of hyperlipidemia.Bioorg. Med. Chem.,2007; 15(14): 4674-4699.
  33. Arnold, M.A.,Swanson, B.J.,Crowder, C.D.,Frankel, W.L.,Lam-Himlin, D.,Singhi, A.D.,Stanich, P.P.,Arnold, C.A. Colesevelam and colestipol: novel medication resins in the gastrointestinal tract. Am. J. Surg. Pathol.; 2014; 38(11):1530-7.
  34. Safeer, R. S., Lacivita, C.L. Choosing drug therapy for patients with hyperlipidemia.Am. Fam. Physician., 2000; 61(11): 3371-82.
  35. Fruchart, J-C., Staels, B., Dallongeville, J., Auwerx, J., Schoonjans, K., Leitersdorf, E. Mechanism of action of fibrates on lipid and lipoprotein metabolism.Circulation.,1998; 98(19): 2088-2093
  36. Martin, G., Schoonjans, K., Lefebvre, A., Staels, B., Auwerx, J. Coordinate regulation of the expression of the fatty acid transporter protein (FATP) and acyl CoA synthetase (ACS) genes by PPARα and PPARγ activators. J.Biol. Chem., 1997;272:28210–28217.
  37. Caslake, M., Packard, C., Gaw, E., Murray, E., Griffin, B., Vallance, B., Shepherd, J. Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia.Arterioscler.Thromb. Vasc. Biol., 1993; (13): 702–711.
  38. Berthou, L., Duverger, N., Emmanuel, F., Langoue¨t, S., Auwerx, J., Guillouzo, A., Fruchart, J-C., Rubin, E., Dene`fle, P., Staels, B., Branellec, D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apo A-I transgenic mice.J. Clin. Invest., 1996; 97(11): 2408 –2416.
  39. Carlson, L.A. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review.J. Intern. Med.,2005;258(2):94-114.
  40. Nutescu, E. A., Shapiro, N. L. Ezetimibe: a selective cholesterol absorption inhibitor. Pharmacotherapy., 2003; 23(11): 1463-74.
  41. Denke, M., Pearson, T., McBride, P. Ezetimibe added to ongoing statin therapy improves LDL-C goal attainment and lipid profile in patients with diabetes or metabolic syndrome. Diab. Vasc. Dis. Res., 2006; 3(2): 93–102.
  42. Altmann, S. W., Davis, H. R., Zhu, L. J. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science., 2004; 303(5661): 1201–1204.
  43. Pattis, P., Wiedermann, C. J. Ezetimibe-associated immune thrombocytopenia.Ann. Pharmacother., 2008; 42(3): 430-433.
  44. Llaverías, G., Laguna, J. C., Alegret, M. Pharmacology of the ACAT inhibitor avasimibe (CI-1011).Cardiovasc. Drug Rev.,2003; 21(1): 33-50.
  45. López-Farré, A. J., Sacristán, D.,Zamorano-León, J. J., San-Martín, N.,Macaya, C. Inhibition of acyl-CoA cholesterol acyltransferase by F12511 (Eflucimibe): Could it be a new antiatherosclerotic therapeutic?Cardiovasc. Ther.,2008; 26(1): 65–74.
  46. Lee, k.,Cho, S. C., Lee, J. H.,Goo, J., Lee, S. Y.,Boovanahalli, S. K.,Koon, S., Yeo, Y. C., Lee, S-J., Kim, Y. K., Kim, D. H., Choi, Y.,Song, G-Y.Synthesis of a novel series of 2-alkylthio substituted naphthoquinones as potent acyl-CoA: Cholesterol acyltransferase (ACAT) inhibitors.Europ. J. Med. Chem., 2013; 62: 515–525.
  47. Magnin, D. R.,Biller, S. A.,Wetterau, J., Robl, J. A., Dickson, J. K. Jr.,Taunk, P., Harrity, T. W.,Lawrence, R. M.,Sun, C.Q.,Wang, T.,Logan, J.,Fryszman, O.,Connolly, F.,Jolibois, K., Kunselman, L. Microsomal triglyceride transfer protein inhibitors: discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents.Bioorg. Med. Chem. Lett., 2003; 13(7): 1337-1340.
  48. Goldberg, A. S., Hegele, R. A. Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib.Drug Des.Devel.Ther.,2012; 6: 251–259.
  49. Shinkai, H. Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases.Vasc.Health Risk Manag., 2012; (8): 323-331.
  50. Liu, C.-I., Jeng, W.-Y., Chang, W.-J., Ko, T.-P., Andrew Wang, A. H.-J. Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase.J. Biol. Chem., 2012; 287(22): 18750–18757.
  51. Sharma, A., Slugg, P. H., Hammett, J. L., Jusko, W. J. Clinical pharmacokinetics and pharmacodynamics of a new squalene synthase inhibitor, BMS-188494, in healthy volunteers.J. Clin. Pharmacol.,1998; 38(12): 1116-1121.
  52. Ugawa, T., Kakuta, H., Moritani, H., Matsuda, K., Ishihara, T., Yamaguchi, M., Naganuma, S.,Iizumi, Y.,Shikama, H. YM-53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species. Br. J. Pharmacol.,2000; 131(1): 63-70.
  53. Ma, Z., Chu, C.-H., Cheng, D. A novel direct homogeneous assay for ATP citrate lyase.J. Lipid Res., 2009; 50(10): 2131-2135.
  54. Li, J. J., Wang, H., Tino, J. A.,Robl, J. A., Herpin, T. F., Lawrence, R. M., Biller, S.,Jamil, H., Ponticiello, R., Chen, L. 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors, Bioorg. Med. Chem. Lett.,2007; 17(11): 3208–3211.
  55. Cao, J.,Zhou, Y.,Peng, H.,Huang, X.,Stahler, S.,Suri, V.,Qadri, A.,Gareski, T.,Jones, J.,Hahm, S.,Perreault, M.,McKew, J.,Shi, M.,Xu, X.,Tobin, J. F., Gimeno, R. E. Targeting Acyl-CoA:diacylglycerolacyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases.J. Biol. Chem.,2011; 286(48): 41838-41851.
  56. Horie, M., Sawasaki, Y., Fukuzumi, H., Watanable, K., Lizuka, Y., Tsuchiya, Y., Kamei, T. Hypolipidemic effects of NB-598 in dogs.Atherosclerosis.,1991; 88(2-3): 183-192.
  57. Rozman, D., Monostory, K. Perspectives of the non-statin hypolipidemic agents.Pharmacol.Ther.,2010; 127(1): 19-40.
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