Low Density Lipoprotein

8/9/2019 Low Density Lipoprotein

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Low-density lipoprotein

LDL redirects here. For other uses, seeLDL (disam-biguation).

Low-density lipoprotein(LDL) is one of the five majorgroups oflipoproteins. Lipoproteins are complex parti-cles composed of multiple proteinswhich transport allfatmolecules (lipids) around the body within the wateroutside cells. They are typically composed of 80-100proteins/particle (organized by a singleApoBfor LDLand the larger particles) and transporting about 3,000 to

6,000 fat molecules/particle. The fats carried includecholesterol,phospholipids, andtriglycerides; amounts ofeach quite variable.

The lipoproteins, from largest to smallest (least denseversus more dense compared with the surrounding wa-ter),are chylomicrons (ULDL), very low-density lipopro-tein (VLDL), intermediate-density lipoprotein (IDL),LDL, and high-density lipoprotein(HDL), all particlesfar smaller than human cells. Lipoproteins transfer fatsthrough the bloodstream, then the intracellular (water) toall cells around the body.[1][2]

Increasing concentrations, low to high, of LDL particlesare strongly associated with increasing amounts, low tohigh, ofatherosclerosiswithin the walls of arteries[3] overtime, eventually resulting insudden plaque rupturesandtriggering clots within the artery opening, or a narrow-ing or closing of the opening,i.e.cardiovascular disease,stroke, and othervascular diseasecomplications.

LDL particles (though far different from cholesterol perse) are sometimes referred to as bad cholesterol be-cause they can transport their content of fat moleculesinto artery walls, attract macrophages, and thus driveatherosclerosis. In contrast,HDLparticles (though fardifferent from cholesterol per se) are often called goodcholesterolor healthy cholesterolbecause they can removefat molecules frommacrophagesin the wall ofarteries.[4]

1 Testing

Blood tests commonly report LDL-C: the amount ofcholesterol which is estimated to be contained with LDLparticles, on average, using a formula, the Friedewaldequation. In clinical context, mathematically calculatedestimates of LDL-C are commonly used as an estimate

of howmuch lowdensity lipoproteins are drivingprogres-sion ofatherosclerosis. The problem with this approachis that LDL-C values are commonly discordant with both

direct measurements of LDL-particles and actual rates ofatherosclerosis progression.

Direct LDL measurements are also available and betterreveal individual issues but are less often promoted ordone due to slightly higher costs and being available fromonly acouple of laboratories in the United States. In2008, theADAandACCrecognized direct LDL particlemeasurement byNMRas superior for assessing individ-ual risk of cardiovascular events.[5]

2 Biochemistry

2.1 Structure

Each native LDL particle enables emulsification, i.e. sur-rounding/packaging all fatty acids being carried, enablingthese fats to move around the body within the water out-side cells. Each particle contains a singleapolipoproteinB-100 molecule (Apo B-100, a protein that has 4536amino acidresidues and a mass of 514kDa), along with

80 to 100 additional ancillary proteins. Each LDL hasa highly hydrophobic core consisting of polyunsaturatedfatty acid known as linoleateand hundreds to thousands(about 1500 commonly cited as an average) esterified andnon-esterified cholesterol molecules. This core also car-ries varying numbers of triglycerides and other fats andis surrounded by a shell of phospholipids and unesteri-fied cholesterol, as well as the single copy of Apo B-100.LDL particles are approximately 22 nm (0.00000087 in.)in diameter and have a mass of about 3 milliondaltons.Since LDL particles contain a variable and changingnumber of fatty acid molecules, there is a distributionof LDL particle mass and size.[6] Determining the struc-ture of LDL has been a tough task because of its het-erogeneous structure. The structure of LDL at humanbody temperature in native condition, with a resolutionof about 16 Angstroms using cryo-electron microscopy,has been recently described.[7]

2.2 LDL subtype patterns

LDL particles vary in size and density, and studies haveshown that a pattern that has more small dense LDL par-ticles, calledPattern B, equates to a higher risk factor for

coronary heart disease(CHD) than does a pattern withmore of the larger and less-dense LDL particles (PatternA). This is thought to be because the smaller particles are

1
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2 3 MEDICAL RELEVANCE - ATHEROSCLEROSIS

more easily able to penetrate the endothelium. PatternI, forintermediate, indicates that most LDL particles arevery close in size to the normal gaps in the endothelium(26 nm). According to one study, sizes 19.020.5 nmwere designated as pattern B and LDL sizes 20.622 nmwere designated as pattern A.[8]

Some in the medical community have suggested the cor-respondence between Pattern B and CHD is stronger thanthe correspondence between the LDL number measuredin the standard lipid profile test. Tests to measure theseLDL subtype patterns have been more expensive and notwidely available, so the common lipid profile test is usedmore often.[9]

There has also been noted a correspondence betweenhigher triglyceride levels and higher levels of smaller,denser LDL particles and alternately lower triglyceridelevels and higher levels of the larger, less dense (a.k.a.

buoyant) LDL.

[10][11]

With continued research, decreasing cost, greater avail-ability and wider acceptance of otherlipoprotein subclassanalysisassay methods, including NMR spectroscopy,[12]

research studies have continued to show a stronger cor-relation between human clinically obvious cardiovascu-lar events and quantitatively measured particle concen-trations.

2.3 Transport into the cell

When a cell requires additional cholesterol (beyond itscurrent internalHMGCoAproduction pathway), it syn-thesizes the necessaryLDL receptors, and inserts theminto the plasma membrane. The LDL receptors diffusefreely until they associate withclathrin-coated pits. LDLparticles in the bloodstream bind to these extracellularLDL receptors. The clathrin-coated pits then form vesi-cles that are endocytosed into the cell.

After the clathrin coat is shed, the vesicles deliver theLDL and their receptors to earlyendosomes, onto lateendosomes to lysosomes. Here the cholesterol esters inthe LDL are hydrolysed. The LDL receptors are recy-

cled back to the plasma membrane.

3 Medical relevance - Atheroscle-

rosis

LDL particles are formed as VLDL lipoproteins losetriglyceride throughthe action of lipoprotein lipase (LPL)and they become smaller and denser (i.e. fewer fatmolecules with same protein transport shell), containinga higher proportion of cholesterol esters.[13]

A hereditary form of high LDL is familial hy-percholesterolemia (FH). Increased LDL is termedhyperlipoproteinemia type II (after the dated Fredrickson

classification).

LDLparticles pose a risk for cardiovascular disease whenthey invade theendotheliumand becomeoxidized, sincethe oxidized forms are more easily retained by the pro-teoglycans. A complex set of biochemical reactions reg-

ulates the oxidation of LDL particles, chiefly stimulatedby presence of necrotic cell debries[13] andfree radicalsin the endothelium.

3.1 Role in the innate immune system

LDL lipoproteins interfere with the quorum sensingsystem that upregulates genes required for invasiveStaphylococcus aureusinfection. The mechanism of an-tagonism entails bindingApolipoprotein B, to a S. aureusautoinducerpheromone, preventing signaling through itsreceptor. Mice deficient in apolipoprotein B are more

susceptible to invasive bacterial infection.[14]

3.2 Lowering LDL-C

The mevalonate pathway serves as the basis for thebiosynthesis of many molecules, including cholesterol.The enzyme 3-hydroxy-3-methylglutaryl coenzyme A re-ductase (HMG CoA reductase) is an essential componentand performs the first of 37 steps within the cholesterolproduction pathway, and present in every animal cell.

Keep in mind that LDL-C is not a measurement of ac-tual LDL particles; LDL-C is only an estimate (not mea-sured from the individuals blood sample) of how muchcholesterol is being transported by all LDL particles; ei-ther a smaller concentration of large particles or a highconcentration of small particles. Also keep in mindthat LDL particles carry many fat molecules (typically3,000 to 6,000 fat molecules per LDL particle); this in-cludes cholesterol, triglycerides, phospholipids and oth-ers. Thus even if the hundreds to thousands of cholesterolmolecules within an average LDL particle were mea-sured, this does not reflect the other fat molecules or eventhe number of LDL particles.

3.2.1 Pharmaceutical

Statinsreduce high levels of LDL particles by in-hibiting the enzymeHMG-CoA reductasein cells,the rate-limiting step of cholesterol synthesis. Tocompensate for the decreased cholesterol availabil-ity, synthesis of hepaticLDL receptorsis increased,resulting in an increased clearance of LDL particlesfrom the blood.

Ezetimibereduces intestinal absorption of choles-terol, thus can reduce LDL particle concentrationswhen combined with statins.[18]
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3.3 Importance of antioxidants 3

PCSK9 inhibitors, in phase 3 clinical trials, by sev-eral companies, appear to be far more effective forLDL reduction than the statins, even statins at highdose.

Niacin (B3), lowers LDL by selectively inhibit-ing hepatic diacyglycerol acyltransferase 2, reducingtriglyceride synthesis and VLDL secretion through areceptor HM74[19] and HM74A or GPR109A.[20]

Several CETP inhibitors have been researched toimprove HDL concentrations, but so far, despitedramatically increasing HDL-C, have not had a con-sistent track record in reducing atherosclerosis dis-ease events. Some have increased mortality ratescompared with placebo.

Clofibrateis effective at lowering cholesterol levels,but has been associated with significantly increasedcancer and stroke mortality, despite lowered choles-terol levels.[21] Other, more recently developed andtested fibrates, e.g. fenofibric acid[22] havehadabet-ter track record and are primarily promoted for low-ering VLDL particles (triglycerides), not LDL par-ticles, yet can help some in combination with otherstrategies.

Some Tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alterna-tive non-prescription agents to treat high choles-terol, having been shown in vitro to have an effect.In particular, gamma-tocotrienol appears to be an-other HMG-CoA reductase inhibitor, and can re-duce cholesterol production.[23] As with statins, thisdecrease in intra-hepatic (liver) LDL levels may in-duce hepatic LDL receptor up-regulation, also de-creasing plasma LDL levels. As always, a key is-sue is how benefits and complications of such agentscompare with statinsmolecular tools that havebeen analyzed in large numbers of human researchand clinical trials since the mid-1970s.

Phytosterols are widely recognized as having aproven LDL cholesterol lowering efficacy.[24] Cur-rent supplemental guidelines recommend doses ofphytosterols in the 1.6-3.0 grams per day range(Health Canada, EFSA, ATP III,FDA) with a re-cent meta-analysis demonstrating an 8.8% reductionin LDL-cholesterol at a mean dose of 2.15 gramper day.[25] However, plant sterols and stanols, ifabsorbed (intestinal cells generally block), greatlyaccelerate progression of atherosclerosis more thancholesterol delivered into the arterial walls bylipoprotein particles.

Insulin induces HMG-CoA reductase activity,whereasglucagondiminishes HMG-CoA reductase

activity.[26] While glucagon production is stimulatedby dietary protein ingestion, insulin production isstimulated by dietary carbohydrate. The rise of in-sulin is, in general, determined by the digestion ofcarbohydratesintoglucoseand subsequent increasein serum glucose levels. In non-diabetics, glucagon

levels are very low when insulin levels are high; how-ever, those who have become diabetic no longer sup-press glucagon output after eating.

A ketogenic diet may havesimilar response to takingniacin(lowered LDL and increased HDL) throughbeta-hydroxybutyrate, aketonebody, coupling theniacin receptor (HM74A).[20]

Lowering the blood lipid concentration oftriglycerides helps lower the concentration of

small LDL particles, because fatty-acid rich VLDLparticles convert in the bloodstream into smalldense LDL particles.

3.2.2 Lifestyle

The most effective approach has been minimizingfat stores located inside theabdominal cavity(vis-ceral body fat) in addition to minimizing total bodyfat. Visceral fat, which is more metabolically ac-tive than subcutaneous fat, has been found to pro-

ducemany enzymatic signals, e.g.resistin, which in-creaseinsulin resistanceand circulating VLDL par-ticle concentrations, thus both increasing LDL parti-cle concentrations and accelerating the developmentofDiabetes Mellitus.

A 2004 pilot study of Garcinia Cambogia saw thattest subjects who took Garcinia Cambogia reducedtheir level of LDL cholesterol by an average of14%, whilst the control group saw only a 0.8%reduction.[27] The main ingredient in Garcinia Cam-bogia and other tropical fruits isHydroxycitric acid.

3.3 Importance of antioxidants

Because LDL particles appear harmless until they arewithin the blood vessel walls and oxidized by freeradicals,[28] it is postulated that ingesting antioxidantsand minimizing free radical exposure may reduce LDLscontribution to atherosclerosis, though results are notconclusive.[29][30] Studies have reported the benefits ofgreen tea in helping to reduce LDL; some studies havefocused on theantioxidantqualities of the unfermented

green tea leaves,[31] others looked at green-tea com-pounds called catechins which are thought to decreasecholesterol absorption in the gut.[32]
https://en.wikipedia.org/wiki/Antioxidanthttps://en.wikipedia.org/wiki/Antioxidantshttps://en.wikipedia.org/wiki/Hydroxycitric_acidhttps://en.wikipedia.org/wiki/Diabetes_Mellitushttps://en.wikipedia.org/wiki/Insulin_resistancehttps://en.wikipedia.org/wiki/Resistinhttps://en.wikipedia.org/wiki/Visceral_fathttps://en.wikipedia.org/wiki/Abdominal_cavityhttps://en.wikipedia.org/wiki/Triglycerideshttps://en.wikipedia.org/wiki/Ketonehttps://en.wikipedia.org/wiki/Niacinhttps://en.wikipedia.org/wiki/Ketogenic_diethttps://en.wikipedia.org/wiki/Glucosehttps://en.wikipedia.org/wiki/Carbohydrateshttps://en.wikipedia.org/wiki/Glucagonhttps://en.wikipedia.org/wiki/Insulinhttps://en.wikipedia.org/wiki/Phytosterolshttps://en.wikipedia.org/wiki/Tocotrienolhttps://en.wikipedia.org/wiki/Clofibratehttps://en.wikipedia.org/wiki/Triglyceridehttps://en.wikipedia.org/wiki/Niacin


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4 4 ESTIMATION OF LDL PARTICLES VIA CHOLESTEROL CONTENT

4 Estimation of LDL particles via

cholesterol content

Chemical measures of lipid concentration have long beenthe most-used clinical measurement, not because they

have the best correlation with individual outcome, butbecause these lab methods are less expensive and morewidely available.

The lipid profile does not measure LDL particles. Itonly estimates them using the Friedewald equation[11][33]

by subtracting the amount of cholesterol associated withother particles, such asHDLandVLDL, assuming a pro-longed fasting state, etc.:

L CH kT

whereHis HDL cholesterol,Lis LDL choles-terol,Cis total cholesterol,Tare triglycerides,

and k is 0.20 if the quantities are measured inmg/dl and 0.45 if in mmol/l.

There are limitations to this method, most notably thatsamples must be obtained after a 12 to 14 h fast andthat LDL-C cannot be calculated if plasma triglycerideis >4.52 mmol/L (400 mg/dL). Even at triglyceridelevels 2.5 to 4.5 mmol/L, this formula is consideredinaccurate.[34] If both total cholesterol and triglyceridelevels are elevated then a modified formula, with quan-tities in mg/dl, may be used

L = CH 0.16T

This formula provides an approximation with fair accu-racy for most people, assuming the blood was drawn afterfasting for about 14 hours or longer, but does not revealthe actual LDL particle concentration because the per-centage of fat molecules within the LDL particles whichare cholesterol varies, as much as 8:1 variation.

However, the concentration of LDL particles, and to alesser extent their size, has a stronger and consistent cor-relation with individual clinical outcome than the amountof cholesterol within LDL particles, even if the LDL-Cestimation is approximately correct. There is increasingevidence and recognition of the value of more targetedand accurate measurements of LDL particles. Specif-ically, LDL particle number (concentration), and to alesser extent size, have shown slightly stronger correla-tions with atherosclerotic progression and cardiovascu-lar events than obtained using chemical measures of theamount of cholesterol carried by the LDL particles.[35]

It is possible that the LDL cholesterol concentration canbe low, yet LDL particle number high and cardiovascularevents rates are high. Correspondingly, it is possible thatLDL cholesterol concentration can be relatively high, yet

LDL particle number low and cardiovascular events arealso low. If LDL particle concentration is used to pre-dict cardiovascular events, many other correlates of these

clinical outcomes, such asdiabetes mellitus, obesity andsmoking, lose most of their predictive accuracy.

4.1 Normal ranges

In the USA, the American Heart Association, NIH,andNCEPprovide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk forheart disease. As of about 2005, these guidelineswere:[36][37][38]

Over time, with more clinical research, these recom-mended levels keep being reduced because LDL reduc-tion, including to abnormally low levels, was the most ef-fective strategy for reducing cardiovascular death rates inone largedouble blind, randomized clinical trial of menwith hypercholesterolemia;[39] far more effective than

coronary angioplasty/stenting or bypass surgery

[40]

For instance, for people with known atherosclerosis dis-eases, the 2004 updated American Heart Association,NIH and NCEP recommendations are for LDL levels tobe lowered to less than 70 mg/dL, unspecified how muchlower. This low level of less than 70 mg/dL was rec-ommended for primary prevention of 'very-high risk pa-tients and in secondary prevention as a 'reasonable fur-ther reduction'. Lack of evidence for such a recommen-dation is discussed in an article in theAnnals of internalmedicine.[41] It should also be noted that statin drugs in-volved in such clinical trials havenumerous physiological

effectsbeyond simply the reduction of LDL levels.It has been estimated from the results of multiple hu-man pharmacologic LDL lowering trials that LDL shouldbe lowered to about 50 to reduce cardiovascular eventrates to near zero. For reference, from longitudinal pop-ulation studies following progression of atherosclerosis-related behaviors from early childhood into adulthood, ithas been discovered that the usual LDL in childhood, be-fore the development offatty streaks, is about 35 mg/dL.However, all the above values refer to chemical measuresof lipid/cholesterol concentration within LDL, not mea-sured Low Density Lipoprotein concentrations, the accu-

rate approach.The feasibility of these figures has been questioned bysceptics, claiming that many members of the AHA andNIH are heavily associated with pharmaceutical compa-nies giving them bias towards lowering cholesterol levelsand such guidelines giving rise to increased use of choles-terol lowering medicine such as statins.

A study was conducted measuring the effects of guide-line changes on LDL cholesterol reporting and controlfor diabetes visits in the US from 1995 to 2004. It wasfound that although LDL cholesterol reporting and con-trol for diabetes and coronary heart disease visits im-

proved continuously between 1995 and 2004, neither the1998 ADA guidelines nor the 2001 ATP III guidelinesincreasedLDL cholesterolcontrol for diabetes relative to
http://www.cholesterolverlagen.nu/bloedcholesterol-verlagen/ldl-bloedcholesterol-verlagen.phphttps://en.wikipedia.org/wiki/Fatty_streakshttps://en.wikipedia.org/wiki/Pleiotropy_(drugs)https://en.wikipedia.org/wiki/Pleiotropy_(drugs)https://en.wikipedia.org/wiki/Annals_of_internal_medicinehttps://en.wikipedia.org/wiki/Annals_of_internal_medicinehttps://en.wikipedia.org/wiki/American_Heart_Associationhttps://en.wikipedia.org/wiki/Double_blindhttps://en.wikipedia.org/wiki/Coronary_heart_diseasehttps://en.wikipedia.org/wiki/National_Cholesterol_Education_Programhttps://en.wikipedia.org/wiki/National_Institutes_of_Healthhttps://en.wikipedia.org/wiki/American_Heart_Associationhttps://en.wikipedia.org/wiki/Diabetes_mellitushttps://en.wikipedia.org/wiki/Very_low-density_lipoproteinhttps://en.wikipedia.org/wiki/High_density_lipoprotein


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5

coronary heart disease.[42]

Moreover, there are publications[43] regarding the risks oflow-LDL cholesterol too.

5 Direct measurement of LDL par-ticle concentrations

There are several competing methods for measurementof lipoprotein particle concentrations and size. The ev-idence is that the NMR methodology (developed, auto-mated & greatly reduced in costs while improving accu-racy as pioneered byJim Otvosand associates) resultsin a 22-25% reduction in cardiovascular events withinjust a single year,[44] contrary to the longstanding claimsby many in the medical industry that the superiorityover existing methods was weak, even by statements ofsome proponents.[45] Direct LDL particle measurementbyNMRwas mentioned by theADAandACC, in a 28March 2008 joint consensus statement,[46] as having ad-vantages for predicting individual risk of atherosclerosisdisease events, but the statement noted that the test isless widely available (single vendor which accepts samplefrom world-wide), is more expensive (about $80.00 USwithout insurance coverage) and it is "...unclear whetherLDL particle size measurements add value to measure-ment of LDL particle concentration, an issue which Li-poScience consultants also tend to agree with (yet alsohas little to do with the value of measuring LDL particles

vs. ApoBvs. cholesterol). Since the later 1990s, be-cause of the development of NMR measurements, it hasbeen possible to clinically measure lipoprotein particlesat lower cost [under $100 US (including shipping) & de-ceasing; versus the previous costs of >$400 to >$5,000]and higher accuracy. There are also other (less expen-sive) homogeneous assays for LDL, however most onlyestimate LDL.

Using NMR, as pioneered by researcherJim Otvosandthe North Carolina State University academic researchspinoff company LipoScience, the total LDL particleconcentrations, in nmol/L plasma, are typically subdi-

vided by percentiles referenced to the 5,382 men andwomen, not on any lipid medications, who are partici-pating in the MESA trial.[47]

5.1 Optimal ranges

The LDL particle concentrations are typically catego-rized by percentiles, 95% groupsof the people participatingandbe-ing tracked in the MESA trial, a medical research studysponsored by the United States National Heart, Lung, and

Blood Institute.The lowest incidence of atherosclerotic events over timeoccurs within the


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6 7 FOOTNOTES

[2] Dashty M, Motazacker MM, Levels J, de Vries M, Mah-moudi M, Peppelenbosch MP, Rezaee F. (2014). Pro-teome of human plasma very low-density lipoprotein andlow-density lipoprotein exhibits a link with coagulationand lipid metabolism..Thromb Haemost.23 (111): 518530.doi:10.1160/TH13-02-0178.PMID 24500811.

[3] http://www.nejm.org/doi/full/10.1056/NEJM198705283162204

[4] LDL and HDL Cholesterol: Whats Bad and WhatsGood?

[5] John D. Brunzell, MD, FACP, Michael Davidson, MD,FACC, Curt D. Furberg, MD, PhD, Ronald B. Gold-berg, MD, Barbara V. Howard, PhD, James H. Stein, MD,FACC, FACP and Joseph L. Witztum, MD LipoproteinManagement in Patients With Cardiometabolic Risk, JAm Coll Cardiol, 2008; 51:1512-1524.

[6] Segrest JP, Jones MK, De Loof H, Dashti N (September2001).Structure of apolipoprotein B-100 in low densitylipoproteins. Journal of Lipid Research 42 (9): 134667.PMID 11518754.

[7] Kumar V, Butcher SJ, Katrina O,Engelhardt P,HeikkonenJ, Kaski K, Ala-Korpela M, Kovanen PT. (May 2011).Three-Dimensional cryoEM Reconstruction of Na-tive LDL Particles to 16 Resolution at Physiologi-cal Body Temperature. PLoS ONE 6 (5): e18841.doi:10.1371/journal.pone.0018841. PMC 3090388.PMID 21573056.

[8] http://onlinelibrary.wiley.com/doi/10.1002/clc.4960280510/pdf

[9] http://www.msnbc.msn.com/id/35058896/ns/health-heart_health/t/bad-cholesterol-its-not-what-you-think/#.T4Gkub_Owrg[]

[10] Superko HR, Nejedly M, Garrett B (2002). Small LDLand its clinical importance as a new CAD risk factor: afemale case study. Progress in Cardiovascular Nursing17 (4): 16773.doi:10.1111/j.0889-7204.2002.01453.x.PMID 12417832.

[11] Warnick GR, Knopp RH, Fitzpatrick V, Branson L (Jan-uary 1990). Estimating low-density lipoprotein choles-

terol by the Friedewald equation is adequate for classify-ing patients on the basis of nationally recommended cut-points. Clinical Chemistry 36 (1): 159.PMID2297909.

[12] Otvos J (June 1999). Measurement of triglyceride-rich lipoproteins by nuclear magnetic resonance spec-troscopy. Clin Cardiol 22 (6 Suppl): II217.doi:10.1002/clc.4960221405.PMID 10376193.

[13] http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/lipoprot.htm

[14] PetersonMM, Mack JL, Hall PR, et al. (December 2008).Apolipoprotein B Is an innate barrier against invasive

Staphylococcus aureus infection. Cell Host & Microbe4(6): 55566. doi:10.1016/j.chom.2008.10.001. PMC2639768.PMID 19064256.

[15] http://www.nhlbi.nih.gov/health-pro/guidelines/current/cholesterol-guidelines/

[16] https://www.acli.com/Events/Documents/Tue22812%20-%20Lipidology%20-%20Pamela%20Morris.pdf

[17] Consumer Reports; Drug Effectiveness Review Project

(March 2013), Evaluating statin drugs to treat HighCholesterol and Heart Disease: Comparing Effectiveness,Safety, and Price, Best Buy Drugs(Consumer Reports):9, retrieved 27 March 2013, which cites

United States Department of Health and HumanServices;NationalHeart, Lung, and BloodInstitute;National Institutes of Health (June 2005).NHLBI,High BloodCholesterol: WhatYou Need to Know.nhlbi.nih.gov. Retrieved 27 March 2013.

[18]

[19] Meyers CD, Kamanna VS, Kashyap ML (December

2004). Niacin therapy in atherosclerosis.Current Opin-ion in Lipidology 15 (6): 65965.doi:10.1097/00041433-200412000-00006.PMID 15529025.

[20] Soudijn W, van Wijngaarden I, Ijzerman AP (May2007). Nicotinic acid receptor subtypes and their lig-ands. Medicinal Research Reviews 27 (3): 41733.doi:10.1002/med.20102.PMID 17238156.

[21] WHO cooperative trial on primary prevention of is-chemic heart disease with clofibrate to lower serumcholesterol: final mortality follow-up. Report of the Com-mittee of Principal Investigators.Lancet2(8403): 6004. September 1984.PMID 6147641.

[22] http://www.rxabbott.com/pdf/trilipix_pi.pdf

[23] Song, B.L.; DeBose-Boyd, R.A. (2006). Insig-Dependent Ubiquitination and Degradation of 3-Hydroxy-3-Methylglutaryl Coenzyme A ReductaseStimulated by Delta- and Gamma-Tocotrienols.J. Biol. Chem. 281 (35): 2505425601.doi:10.1074/jbc.M605575200.PMID 16831864.

[24] European Food Safety Authority, Journal (2010).Scientific opinion on the substantiation of health claimsrelated to plant sterols and plant stanols and maintenanceof normal blood cholesterol concentrations.

[25] Demonty, I; Ras, RT, van der Knaap, HC, Duchateau,GS, Meijer, L, Zock, PL, Geleijnse, JM, Trautwein,EA (Feb 2009). Continuous dose-response relation-ship of the LDL-cholesterol-lowering effect of phytos-terol intake.. The Journal of nutrition 139 (2): 27184.doi:10.3945/jn.108.095125.PMID 19091798.

[26] Regulation of Cholesterol Synthesis

[27] http://www.omegalife.com.au/garcinia-cambogia

[28] Inhibition of in vitro human LDL oxidation by pheno-lic antioxidants from grapes and wines. Teissedre, P.L.

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[47]

8 External links

Fat (LDL) Degradation: PMAPThe ProteolysisMap-animation

Adult Treatment Panel III Full Report

ATP III Update 2004 O'Keefe JH, Cordain L, Harris WH, Moe RM, Vo-

gel R (June 2004). Optimal low-density lipopro-tein is 50 to 70 mg/dl: lower is better andphysiologically normal. Journal of the Amer-ican College of Cardiology 43 (11): 21426.doi:10.1016/j.jacc.2004.03.046.PMID 15172426.
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8 9 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

9 Text and image sources, contributors, and licenses

9.1 Text

Low-density lipoproteinSource: http://en.wikipedia.org/wiki/Low-density%20lipoprotein?oldid=643831008Contributors:Kpjas, BryanDerksen, Andre Engels, Rgamble, Mbmanie, Gabbe, Milkfish, Tristanb, Charles Matthews, Maximus Rex, Joy, Jeffq, PuzzletChung, Rob-bot, Stewartadcock, Mr-Natural-Health, Kd4ttc, Fuelbottle, Diberri, Giftlite, DocWatson42, Ksheka, Everyking, Jfdwolff, Bobblewik,Erich gasboy, Alexf, Beland, PFHLai, Elektron, Ukexpat, Abdull, Rich Farmbrough, Guanabot, Cacycle, NickVeys, MAlvis, SietseSnel, Smalljim, Davidruben, Richi, Arcadian, Sriram sh, KBi, Unused000701, Googie man, Nereocystis, Arthena, Shoefly, Boyd Steere,Gene Nygaard, Jigsaw, Pol098, Tabletop, BorisTM, Koolkao, Rjwilmsi, Bhadani, Hathawayc, Dvdmon, FlaBot, Jeanpol, Gkelly, Mhk-ing, Roboto de Ajvol, Raelx, Chris Capoccia, Draeco, Bmdavll, Stellis, Dfgriggs, Davidpatrick, Eurosong, Johnsleonard, StuRat, MateoLeFou, Shashikiranu, X-mass, Johnpseudo, SmackBot, Slashme, FlipOne, Stepa, Anastrophe, Cparker, Shai-kun, David.Throop, Tyciol,Chris the speller, Rogermw, KaiserbBot, Xiner, Drphilharmonic, Esb, Ligulembot, Cbamity, Ohconfucius, Dacres, Anlace, Attys, Kuru,Giessauf A, Tim bates, RomanSpa, Novangelis, Viennese Waltz, Gon-no-suke, Robotsintrouble, GeorgeLouis, Peter Soros, Gregory Gai,Johner, Icek, BillO'Slatter, Blindman shady, Thijs!bot, David from Downunder, CopperKettle, RLE64, Plausible deniability, Headbomb,Tonyle, Klausness, AntiVandalBot, WinBot, Qwerty Binary, JAnDbot, RubyQ, Greensburger, Acroterion, Coffee2theorems, Magioladitis,VoABot II, Karkaputto, Peaceandlove666, WhatamIdoing, Allstarecho, Nono64, AgarwalSumeet, Nbauman, Xris0, Mike.lifeguard, Fu-nandtrvl, Butwhatdoiknow, Rmkrauss, Shuvaev, Bdb484, Cloudswrest, Amaher, Nedrutland, Michaeldsuarez, Twooars, Kosigrim, Dv3,Happysailor, Bsherr, My dying wish, Ellusion, Again444555, Iiigoiii, Fess-it, Zbisasimone, ClueBot, Silhign, The Thing That ShouldNot Be, Mild Bill Hiccup, Doseiai2, Edenatude, Auntof6, Dlf723, Pandnh4, Razorflame, SchreiberBike, H.Ameer, Gundog48, Facts707,Noctibus, Kbdankbot, Addbot, DOI bot, Metagraph, Quercus solaris, Lpmtwest, Flakinho, Avono, , Legobot, Luckas-bot, Yobot,TaBOT-zerem, AnomieBOT, Rubinbot, Boonenoob, Bluerasberry, Materialscientist, Pancrat, Citation bot, Xqbot, RegulatorRectifier,

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File:Edit-clear.svg Source: http://upload.wikimedia.org/wikipedia/en/f/f2/Edit-clear.svg License: Public domain Contributors: TheTango! Desktop Project. Original artist:

The people from the Tango! project. And according to the meta-data in the file, specifically: Andreas Nilsson, and Jakub Steiner (althoughminimally).

File:Question_book-new.svg Source: http://upload.wikimedia.org/wikipedia/en/9/99/Question_book-new.svg License: Cc-by-sa-3.0

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