Cholesterol_ Synthesis, Metabolism, Regulation.pdf

7/27/2019 Cholesterol_ Synthesis, Metabolism, Regulation.pdf

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10/26/13 Cholesterol: Synthesis, Metabolism, Regulation

themedicalbiochemistrypage.org/cholesterol.php 3/10

1.Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)

2.HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the

concomitant loss of CO2

4.IPP is converted to squalene

5.Squalene is converted to cholesterol.

Pathway of cholesterol biosynthesis. Synthesis begins with the transport of acetyl-CoA from the mitochondrion tothe cytosol. The rate limiting step occurs at the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reducatase, HMGR

catalyzed step. The phosphorylation reactions are required to solubilize the isoprenoid intermediates in the pathway.

Intermediates in the pathway are used for the synthesis of prenylated proteins, dolichol, coenzyme Q and the side

chain of heme a. The abbreviation "PP" (e.g. isopentenyl-PP) stands for pyrophosphate. Place mouse over

intermediate names to see structure.

Acetyl-CoA units are converted to mevalonate by a series of reactions that begins with the formation of HMG-

CoA. Unlike the HMG-CoA formed during ketone body synthesisin the mitochondria, this form is synthesized in the

cytoplasm. However, the pathway and the necessary enzymes are similar to those in the mitochondria. Two moles of

acetyl-CoA are condensed in a reversal of the thiolase reaction, forming acetoacetyl-CoA. The cytoplasmic thiolase

enzyme involved in cholesterol biosynthesis is acetoacetyl-CoA thiolase encoded by the ACAT2 gene. Although the

bulk of acetoacetyl-CoA is derived via this process, it is possible for some acetoacetate, generated during

ketogenesis, to diffuse out of the mitochondria and be converted to acetoacetyl-CoA in the cytosol via the action of

acetoacetyl-CoA synthetase (AACS). Acetoacetyl-CoA and a third mole of acetyl-CoA are converted to HMG-CoA by

the action of HMG-CoA synthase.

HMG-CoA is converted to mevalonate by HMG-CoA reductase, HMGR (this enzyme is bound in the endoplasmic

reticulum, ER). HMGR absolutely requires NADPH as a cofactor and two moles of NADPH are consumed during the

conversion of HMG-CoA to mevalonate. The reaction catalyzed by HMGR is the rate limiting step of cholesterol

biosynthesis, and this enzyme is subject to complex regulatory controls as discussed below.

Mevalonate is then activated by two successive phosphorylations (catalyzed by mevalonate kinase, and

phosphomevalonate kinase), yielding 5-pyrophosphomevalonate. In humans, mevalonate kinase resides in the cytosol

indicating that not all the reactions of cholesterol synthesis are catalyzed by membrane-associated enzymes as

originally described. After phosphorylation, an ATP-dependent decarboxylation yields isopentenyl pyrophosphate, IPP,

an activated isoprenoid molecule. Isopentenyl pyrophosphate is in equilibrium with its isomer, dimethylallyl

pyrophosphate, DMPP. One molecule of IPP condenses with one molecule of DMPP to generate geranyl

pyrophosphate, GPP. GPP further condenses with another IPP molecule to yield farnesyl pyrophosphate, FPP. Finally,the NADPH-requiring enzyme, squalene synthase catalyzes the head-to-tail condensation of two molecules of FPP,

yielding squalene. Like HMGR, squalene synthase is tightly associated with the ER. Squalene undergoes a two step

cyclization to yield lanosterol. The first reaction is catalyzed by squalene monooxygenase. This enzyme uses NADPH

as a cofactor to introduce molecular oxygen as an epoxide at the 2,3 position of squalene. Through a series of 19

additional reactions, lanosterol is converted to cholesterol.
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The terminal reaction in cholesterol biosynthesis is catalyzed by the enzyme 7-dehydrocholesterol reductase

encoded by the DHCR7 gene. Functional DHCR7 protein is a 55.5 kDa NADPH-requiring integral membrane protein

localized to the microsomal membrane. Deficiency in DHCR7 (due to gene mutations) results in the disorder called

Smith-Lemli-Opitz syndrome, SLOS. SLOS is characterized by increased levels of 7-dehydrocholesterol and reduced

levels (15% to 27% of normal) of cholesterol resulting in multiple developmental malformations and behavioral

problems.

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Regulating Cholesterol Synthesis

Normal healthy adults synthesize cholesterol at a rate of approximately 1g/day and consume approximately

0.3g/day. A relatively constant level of cholesterol in the blood (150200 mg/dL) is maintained primarily by controlling

the level of de novosynthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol.

Cholesterol from both diet and synthesis is utilized in the formation of membranes and in the synthesis of the steroid

hormonesand bile acids. The greatest proportion of cholesterol is used in bile acid synthesis.

The cellular supply of cholesterol is maintained at a steady level by three distinct mechanisms:

1.Regulation of HMGR activity and levels

2.Regulation of excess intracellular free cholesterol through the activity of acyl-CoA:cholesterol acyltransferase,

ACAT

3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDL-mediated reverse

transport.

Regulation of HMGR activity is the primary means for controlling the level of cholesterol biosynthesis. The enzyme

is controlled by four distinct mechanisms: feed-back inhibition, control of gene expression, rate of enzyme degradation

and phosphorylation-dephosphorylation.

The first three control mechanisms are exerted by cholesterol itself. Cholesterol acts as a feed-back inhibitor of

pre-existing HMGR as well as inducing rapid degradation of the enzyme. The latter is the result of cholesterol-induced

polyubiquitination of HMGR and its degradation in the proteosome (see proteolytic degradationbelow). This ability of

cholesterol is a consequence of the sterol sensing domain, SSDof HMGR. In addition, when cholesterol is in excess

the amount of mRNA for HMGR is reduced as a result of decreased expression of the gene. The mechanism by which

cholesterol (and other sterols) affect the transcription of the HMGR gene is described below under regulation of sterol

content.

Regulation of HMGR through covalent modification occurs as a result of phosphorylation and dephosphorylation.

The enzyme is most active in its unmodified form. Phosphorylation of the enzyme decreases its activity. HMGR is

phosphorylated by AMP-activated protein kinase, AMPK (this is not the same as cAMP-dependent protein kinase,

PKA). AMPK itself is activated via phosphorylation. Phosphorylation of AMPK is catalyzed by at least 2 enzymes. The

primary kinase sensitive to rising AMP levels is LKB1. LKB1 was first identified as a gene in humans carrying an

autosomal dominant mutation in Peutz-Jeghers syndrome, PJS. LKB1 is also found mutated in lung adenocarcinomas.

The second AMPK phosphorylating enzyme is calmodulin-dependent protein kinase kinase-beta (CaMKK). CaMKK

induces phosphorylation of AMPK in response to increases in intracellular Ca2+as a result of muscle contraction. Visit

AMPK: The Master Metabolic Regulatorfor more detailed information on the role of AMPK in regulating metabolism.
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Regulation of HMGR by covalent modification. HMGR is most active in the dephosphorylated state.

Phosphorylation is catalyzed by AMP-activated protein kinase, AMPK, (used to be termed HMGR kinase), an

enzyme whose activity is also regulated by phosphorylation. Phosphorylation of AMPK is catalyzed by at least 2

enzymes: LKB1 and CaMKK. Hormones such as glucagon and epinephrine negatively affect cholesterol

biosynthesis by increasing the activity of the inhibitor of phosphoprotein phosphatase inhibitor-1, PPI-1. Conversely,

insulin stimulates the removal of phosphates and, thereby, activates HMGR activity. Additional regulation of HMGR

occurs through an inhibition of its' activity as well as of its' synthesis by elevation in intracellular cholesterol levels.This latter phenomenon involves the transcription factor SREBP described below.

The activity of HMGR is additionally controlled by the cAMP signaling pathway. Increases in cAMP lead to

activation of cAMP-dependent protein kinase, PKA. In the context of HMGR regulation, PKA phosphorylates

phosphoprotein phosphatase inhibitor-1 (PPI-1) leading to an increase in its' activity. PPI-1 can inhibit the activity of

numerous phosphatases including protein phosphatase 2C (PP2C) and PP2A (also called HMGR phosphatase)

which remove phosphates from AMPK and HMGR, respectively. This maintains AMPK in the phosphorylated and

active state, and HMGR in the phosphorylated and inactive state. As the stimulus leading to increased cAMP

production is removed, the level of phosphorylations decreases and that of dephosphorylations increases. The net

result is a return to a higher level of HMGR activity.

Since the intracellular level of cAMP is regulated by hormonal stimuli, regulation of cholesterol biosynthesis is

hormonally controlled. Insulin leads to a decrease in cAMP, which in turn activates cholesterol synthesis. Alternatively,

glucagon and epinephrine, which increase the level of cAMP, inhibit cholesterol synthesis.

The ability of insulin to stimulate, and glucagon to inhibit, HMGR activity is consistent with the effects of these

hormones on other metabolic pathways. The basic function of these two hormones is to control the availability and

delivery of energy to all cells of the body.

Long-term control of HMGR activity is exerted primarily through control over the synthesis and degradation of the

enzyme. When levels of cholesterol are high, the level of expression of the HMGR gene is reduced. Conversely,

reduced levels of cholesterol activate expression of the gene. Insulin also brings about long-term regulation of

cholesterol metabolism by increasing the level of HMGR synthesis.

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Proteolytic Regulation of HMG-CoA Reductase

The stability of HMGR is regulated as the rate of flux through the mevalonate synthesis pathway changes. When theflux is high the rate of HMGR degradation is also high. When the flux is low, degradation of HMGR decreases. This

phenomenon can easily be observed in the presence of the statin drugs as discussed below.

HMGR is localized to the ER and like SREBP (see below) contains a sterol-sensing domain, SSD. When sterol

levels increase in cells there is a concomitant increase in the rate of HMGR degradation. The degradation of HMGR

occurs within the proteosome, a multiprotein complex dedicated to protein degradation. The primary signal directing
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proteins to the proteosome is ubiquitination. Ubiquitin is a 7.6kDa protein that is covalently attached to proteins

targeted for degradation by ubiquitin ligases. These enzymes attach multiple copies of ubiquitin allowing for

recognition by the proteosome. HMGR has been shown to be ubiquitinated prior to its degradation. The primary sterol

regulating HMGR degradation is cholesterol itself. As the levels of free cholesterol increase in cells, the rate of HMGR

degradation increases.

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The Utilization of Cholesterol

Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins. Dietarycholesterol is transported from the small intestine to the liver within chylomicrons. Cholesterol synthesized by the liver,

as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum within LDLs. The

liver synthesizes VLDLs and these are converted to LDLs through the action of endothelial cell-associated lipoprotein

lipase. Cholesterol found in plasma membranes can be extracted by HDLs and esterified by the HDL-associated

enzyme LCAT. The cholesterol acquired from peripheral tissues by HDLs can then be transferred to VLDLs and LDLs

via the action of cholesteryl ester transfer protein (apo-D) which is associated with HDLs. Reverse cholesterol

transportallows peripheral cholesterol to be returned to the liver in LDLs. Ultimately, cholesterol is excreted in the bile

as free cholesterol or as bile salts following conversion to bile acids in the liver.

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Cytochrome P450 Enzymes in Cholesterol Metabolism

Cytochrome P450 enzymes are involved in a diverse array of biological processes that includes lipid, cholesterol,

and steroid metabolism as well as the metabolism of xenobiotics. The now common nomenclature used to designate

P450 enzymes is CYP. There are at least 57 CYP enzymes in human tissues with eight being involved in cholesterol

biosynthesis and metabolism, which includes conversion of cholesterol to bile acids. CYP metabolism of cholesterol

yields several oxysterols that function as biologically active molecules such as in the activation of the liver X receptors(LXRs)and SREBP (see the next section).

CYP3A4:CYP3A4 is also known as glucocorticoid-inducible P450 and nifedipine oxidase. Nifedipine is a

member of the calcium channel blocker drugs used to treat hypertension. CYP3A4 is a major hepatic P450

enzyme and is responsible for the biotransformation of nearly 60% of all commercially available drugs. With

respect to cholesterol metabolism, CYP3A4 catabolizes cholesterol to 4-hydroxycholesterol. This cholesterol

derivative is one of the major circulating oxysterols and is seen at elevated levels in patients treated with anti-

seizure medications such as carbamazepine, phenobarbitol, and phenytoin. The nuclear receptor, pregnane X

receptor (PXR), is known to be an inducer of the CYP3A4 gene.CYP7A1:CYP7A1 is also known as cholesterol 7-hydroxylase and is the rate limiting enzyme in the primary

pathway of bile acid synthesis referred to as the classic pathway. This reaction of bile acid synthesis plays a

major role in hepatic regulation of overall cholesterol balance. Deficiency in CYP7A1 manifests with markedly

elevated total cholesterol as well as LDL, premature gallstones, premature coronary and peripheral vascular

disease. Treatment of this disorder with members of the statin drug family do not alleviated the elevated serum

cholesterol due to the defect in hepatic diversion of cholesterol into bile acids.

CYP7B1:CYP7B1 is also known as oxysterol 7-hydroxylase and is involved in the synthesis of bile acids via

the less active secondary pathway referred to as the acidic pathway. A small percentage (1%) of individuals

suffering from autosomal recessive hereditary spastic paraplegia 5A (SPG5A) have been shown to harbor

mutations in the CYP7B1 gene.

CYP8B1: CYP8B1 is also known as sterol 12a-hydroxylase and is involved in the conversion of 7-

hydroxycholesterol (CYP7A1 product) to cholic acid which is one of two primary bile acids and is derived fromthe classic pathway of bile acid synthesis. The activity of CYP8B1 controls the ratio of cholic acid over

chenodeoxycholic acid in the bile.

CYP27A1:CYP27A1 is also known as sterol 27-hydroxylase and is localized to the mitochondria. CYP27A1

functions with two cofactor proteins called adrenodoxin and adrenodoxin reductase to hydroxylate a variety of

sterols at the 27 position. CYP27A1 is also involved in the diversion of cholesterol into bile acids via the less

active secondary pathway referred to as the acidic pathway. Deficiencies in CYP27A1 result in progressive

neurological dysfunction, neonatal cholestasis, bilateral cataracts, and chronic diarrhea.

CYP39A1:CYP39A1 is also known as oxysterol 7-hydroxylase 2. This P450 enzyme was originally identified in

mice in which the CYP7B1 gene had been knocked out. The preferential substrate for CYP39A1 is 24-

hydroxycholesterol, which is a major product of CYP46A1, which via CYP39A1 action is diverted into bile acid

synthesis.

CYP46A1: CYP46A1 is also known as cholesterol 24-hydroxylase. This enzyme is expressed primarily inneurons of the central nervous system where it plays an important role in metabolism of cholesterol in the brain.

The product of CYP46A1 action if 24S-hydroxycholesterol which can readily traverse the blood-brain-barrier to

enter the systemic circulation. This pathway of cholesterol metabolism in the brain is a part of the reverse

cholesterol transport process and serves as a major route of cholesterol turnover in the brain. 24S-

hydroxycholesterol is a known potent activator of LXRand as such serves as an activator of the expression of
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Cholesterol Free About Cholesterol Blood Cholesterol Cholesterol Level
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About Cholesterol Blood Cholesterol High Cholesterol Is Cholesterol
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activity indicative of enhanced proliferation. These results suggest that a marked reduction in serum LDLs, induced by

reduced cholesterol intake, stimulates enhanced DNA synthesis and cell proliferation.

Drug treatment to lower plasma lipoproteins and/or cholesterol is primarily aimed at reducing the risk of

atherosclerosis and subsequent coronary artery disease that exists in patients with elevated circulating lipids. Drug

therapy usually is considered as an option only if non-pharmacologic interventions (altered diet and exercise) have

failed to lower plasma lipids.

Atorvastatin (Lipitor), Simvastatin (Zocor), Lovastatin (Mevacor):These drugs are fungal HMG-CoA

reductase (HMGR) inhibitors and are members of the family of drugs referred to as the statins. The net result of

treatment is an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells

are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMG-

CoA reductase reaction) is required for the synthesis of other important isoprenoid compounds besides cholesterol,

long-term treatments carry some risk of toxicity. A component of the natural cholesterol lowering supplement, red yeast

rice, is in fact a statin-like compound.

The statins have become recognized as a class of drugs capable of more pharmacologic benefits than just

lowering blood cholesterol levels via their actions on HMGR. Part of the cardiac benefit of the statins relates to their

ability to regulate the production of S-nitrosylated COX-2. COX-2 is an inducible enzyme involved in the synthesis of

the prostaglandins and thromboxanesas well as the lipoxins and resolvins. The latter two classes of compounds are

anti-inflammatory lipids discussed in the Lipid-Derived Inflammatory Modulatorspage. Evidence has shown that statins

activate inducible nitric oxide synthase (iNOS) leading to nitrosylation of COX-2. The S-nitrosylated COX-2 enzyme

produces the lipid compound 15R-hydroxyeicosatetraenoic acid (15R-HETE) which is then converted via the action of

5-lipoxygenase (5-LOX) to the epimeric lipoxin, 15-epi-LXA4. This latter compound is the same as the aspirin-

triggered lipoxin (ATL) that results from the aspirin-induced acetylation of COX-2. Therefore, part of the beneficial

effects of the statins is exerted via the actions of the lipoxin family of anti-inflammatory lipids.Additional anti-inflammatory actions of the statins result from a reduction in the prenylation of numerous pro-

inflammatory modulators. Prenylation refers to the addition of the 15 carbon farnesyl group or the 20 carbon

geranylgeranyl group to acceptor proteins. The isoprenoid groups are attached to cysteine residues at the carboxy

terminus of proteins in a thioether linkage (C-S-C). A common consensus sequence at the C-terminus of prenylated

proteins has been identified and is composed of CAAX, where C is cysteine, A is any aliphatic amino acid (except

alanine) and X is the C-terminal amino acid. In addition to numerous prenylated proteins that contain the CAAX

consensus, prenylation is known to occur on proteins of the RAB family of RAS-related G-proteins. There are at least

60 proteins in this family that are prenylated at either a CC or CXC element in their C-termini. The RAB family of

proteins are involved in signaling pathways that control intracellular membrane trafficking. The prenylation of proteins

allows them to be anchored to cell membranes. In addition to cell membrane attachment, prenylation is known to be

important for protein-protein interactions. Thus, inhibition of this post-translational modification by the statins interferes

with the important functions of many signaling proteins which is manifest by inhibition of inflammatory responses.

Some of the effects on immune function that have been attributed to the statins are attenuation of autoimmunedisease, inhibition of T-cell proliferation, inhibition of inflammatory co-stimulatory molecule expression, decreases in

leukocyte infiltration, and promotion of a shift in cytokine profiles of helper T-cell types from Th1 to Th2. Th1 cells are

involved in cell-mediated immunity processes, whereas, Th2 cells are involved in humoral immunity process. The

cytokinesproduced by Th2 cells include IL-4, IL-5, IL-10 and IL-13 and these trigger B cells to switch to IgE production

and to activate eosinophils.

Nicotinic acid:Nicotinic acid reduces the plasma levels of both VLDLs and LDLs by inhibiting hepatic VLDL

secretion, as well as suppressing the flux of FFA release from adipose tissue by inhibiting lipolysis. In addition,

nicotinic administration strongly increases the circulating levels of HDLs. Patient compliance with nicotinic acid

administration is sometimes compromised because of the unpleasant side-effect of flushing (strong cutaneous

vasodilation). Recent evidence has shown that nicotinic acid binds to and activates the G-protein coupled receptor

identified as GPR109A (also called HM74A or PUMA-G). The identity of a receptor to which nicotinic acid binds allows

for the development of new drug therapies that activate the same receptor but that may lack the negative side-effect of

flushing associated with nicotinic acid. Because of its ability to cause large reductions in circulating levels ofcholesterol, nicotinic acid is used to treat Type II, III, IV and V hyperlipoproteinemias.

Gemfibrozil (Lopid), Fenofibrate (TriCor):These compounds (called fibrates) are derivatives of fibric acid

and although used clinically since the 1930's were only recently discovered to exert some of their lipid-lowering effects

via the activation of peroxisome proliferation. Specifically, the fibrates were found to be activators of the peroxisome

proliferator-activated receptor- (PPAR)class of proteins that are classified as nuclear receptor co-activators. The

naturally occurring ligands for PPAR are leukotriene B4(LTB4, see the Lipid Synthesis page), unsaturated fatty acids

and oxidized components of VLDLs and LDLs. The PPARs interact with another receptor family called the retinoid X

receptors (RXRs) that bind 9-cis-retinoic acid. Activation of PPARs results in modulation of the expression of genes

involved in lipid metabolism. In addition the PPARs modulate carbohydrate metabolism and adipose tissue

differentiation. Fibrates result in the activation of PPAR in liver and muscle. In the liver this leads to increased -

oxidation of fatty acids, thereby decreasing the liver's secretion of triacylglycerol- and cholesterol-rich VLDLs, as well

as increased clearance of chylomicron remnants, increased levels of HDLs and increased lipoprotein lipase activity

which in turn promotes rapid VLDL turnover.

Cholestyramine or colestipol (resins):These compounds are nonabsorbable resins that bind bile acids which

are then not reabsorbed by the liver but excreted. The drop in hepatic reabsorption of bile acids releases a feedback

inhibitory mechanism that had been inhibiting bile acid synthesis. As a result, a greater amount of cholesterol is

converted to bile acids to maintain a steady level in circulation. Additionally, the synthesis of LDL receptors increases

to allow increased cholesterol uptake for bile acid synthesis, and the overall effect is a reduction in plasma cholesterol.
http://themedicalbiochemistrypage.org/lipid-synthesis.php#eicosanoidshttp://themedicalbiochemistrypage.org/signal-transduction.php#insidehttp://themedicalbiochemistrypage.org/ppar.phphttp://themedicalbiochemistrypage.org/growth-factors.php#table2http://themedicalbiochemistrypage.org/protein-modifications.php#prenylationhttp://themedicalbiochemistrypage.org/aspirin.phphttp://themedicalbiochemistrypage.org/lipid-synthesis.php#eicosanoidshttp://themedicalbiochemistrypage.org/lipoproteins.php#pharmacology


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h di lbi h i / h l l h 10/10

This treatment is ineffective in homozygous FH patients, since they are completely deficient in LDL receptors.

Ezetimibe:This drug is sold under the trade names Zetia or Ezetrol and is also combined with the statin drug

simvastatin and sold as Vytorin or Inegy. Ezetimibe functions to reduce intestinal absorption of cholesterol, thus

effecting a reduction in circulating cholesterol. The drug functions by inhibiting the intestinal brush border transporter

involved in absorption of cholesterol. This transporter is known as Niemann-Pick type C1-like 1 (NPC1L1). NPC1L1 is

also highly expressed in human liver. The hepatic function of NPC1L1 is presumed to limit excessive biliary cholesterol

loss. NPC1L1-dependent sterol uptake is regulated by cellular cholesterol content. In addition to the cholesterol

lowering effects that result from inhibition of NPC1L1, its' inhibition has been shown to have beneficial effects on

components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to

atherosclerosis. Ezetimibe is usually prescribed for patients who cannot tolerate a statin drug or a high dose statin

regimen. There is some controversy as to the efficacy of ezetimibe at lowering serum cholesterol and reducing theproduction of fatty plaques on arterial walls. The combination drug of ezetimibe and simvastatin has shown efficacy

equal to or slightly greater than atorvastatin (Lipitor) alone at reducing circulating cholesterol levels.

New Approaches:Numerous epidemiological and clinical studies over the past 10 years have demonstrated a

direct correlation between the circulating levels of HDL cholesterol (most often abbreviated HDL-c) and a reduction in

the potential for atherosclerosis and coronary heart disease (CHD). Individuals with levels of HDL above 50mg/dL are

several time less likely to experience CHD than individuals with levels below 40mg/dL. In addition, clinical studies in

which apolipoprotein A-I (apoA-I), the predominant protein component of HDL-c) or reconstituted HDLs are infused

into patients raises circulating HDL levels and reduces the incidence of CHD. Thus, there is precedence for therapies

aimed at raising HDL levels in the treatment and prevention of atherosclerosis and CHD. Unfortunately current

therapies only modestly elevate HDL levels. Both the statins and the fibrates have only been shown to increase HDL

levels between 520% and niacin is poorly tolerated in many patients. Therefore, alternative strategies aimed at

increasing HDL levels are being tested. Cholesterol ester transfer protein (CETP) is secreted primarily from the liver

and plays a critical role in HDL metabolism by facilitating the exchange of cholesteryl esters (CE) from HDL fortriglycerides (TG) in apoB containing lipoproteins, such as LDL and VLDL. The activity of CETP directly lowers the

cholesterol levels of HDLs and enhances HDL catabolism by providing HDLs with the TG substrate of hepatic lipase.

Thus, CETP plays a critical role in the regulation of circulating levels of HDL, LDL, and apoA-I. It has also been shown

that in mice naturally lacking CETP most of their cholesterol is found in HDL and these mice are relatively resistant to

atherosclerosis. The potential for the therapeutic use of CETP inhibitors in humans was first suggested when it was

discovered in 1985 that a small population of Japanese had an inborn error in the CETP gene leading to

hyperalphalipoproteinemia and very high HDL levels. To date three CETP inhibitors have been used in clinical trials.

These compounds are anacetrapib, torcetrapib, and dalcetrapib. Although torcetrapib is a potent inhibitor of CETP, its'

use has been discontinued due to increased negative cardiovascular events and death rates in test subjects.

Treatment with dalcetrapib results in increases in HDL (1937%) and a modest decrease (6%) in LDL levels.

Treatment with anacetrapib results in a significant increase in both HDL (130%) and LDL (40%). Anacetrapib is

currently in phase III clinical studies.

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