Low-density lipoprotein

LDL redirects here. For other uses, see LDL (disam- direct measurements of LDL-particles and actual rates of
biguation).
atherosclerosis progression.
Direct LDL measurements are also available and better
reveal individual issues but are less often promoted or
done due to slightly higher costs and being available from
only a couple of laboratories in the United States. In
2008, the ADA and ACC recognized direct LDL particle
measurement by NMR as superior for assessing individual risk of cardiovascular events.[5]

Low-density lipoprotein (LDL) is one of the ve major

groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all
fat molecules (lipids) around the body within the water
outside cells. They are typically composed of 80-100
proteins/particle (organized by a single ApoB for LDL
and the larger particles) and transporting about 3,000 to
6,000 fat molecules/particle. The fats carried include
cholesterol, phospholipids, and triglycerides; amounts of
each quite variable.

2 Biochemistry

The lipoproteins, from largest to smallest (least dense

versus more dense compared with the surrounding water), are chylomicrons (ULDL), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL),
LDL, and high-density lipoprotein (HDL), all particles
far smaller than human cells. Lipoproteins transfer fats
through the bloodstream, then the intracellular (water) to
all cells around the body.[1][2]

2.1 Structure
Each native LDL particle enables emulsication, i.e. surrounding/packaging all fatty acids being carried, enabling
these fats to move around the body within the water outside cells. Each particle contains a single apolipoprotein
B-100 molecule (Apo B-100, a protein that has 4536
amino acid residues and a mass of 514 kDa), along with
80 to 100 additional ancillary proteins. Each LDL has
a highly hydrophobic core consisting of polyunsaturated
fatty acid known as linoleate and hundreds to thousands
(about 1500 commonly cited as an average) esteried and
non-esteried cholesterol molecules. This core also carries varying numbers of triglycerides and other fats and
is surrounded by a shell of phospholipids and unesteried 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 million daltons.
Since LDL particles contain a variable and changing
number of fatty acid molecules, there is a distribution
of LDL particle mass and size.[6] Determining the structure of LDL has been a tough task because of its heterogeneous structure. The structure of LDL at human
body temperature in native condition, with a resolution
of about 16 Angstroms using cryo-electron microscopy,
has been recently described.[7]

Increasing concentrations, low to high, of LDL particles

are strongly associated with increasing amounts, low to
high, of atherosclerosis within the walls of arteries[3] over
time, eventually resulting in sudden plaque ruptures and
triggering clots within the artery opening, or a narrowing or closing of the opening, i.e. cardiovascular disease,
stroke, and other vascular disease complications.
LDL particles (though far dierent from cholesterol per
se) are sometimes referred to as bad cholesterol because they can transport their content of fat molecules
into artery walls, attract macrophages, and thus drive
atherosclerosis. In contrast, HDL particles (though far
dierent from cholesterol per se) are often called good
cholesterol or healthy cholesterol because they can remove
fat molecules from macrophages in the wall of arteries.[4]

Testing

2.2 LDL subtype patterns

Blood tests commonly report LDL-C: the amount of

cholesterol which is estimated to be contained with LDL
particles, on average, using a formula, the Friedewald
equation. In clinical context, mathematically calculated
estimates of LDL-C are commonly used as an estimate
of how much low density lipoproteins are driving progression of atherosclerosis. The problem with this approach
is that LDL-C values are commonly discordant with both

LDL particles vary in size and density, and studies have

shown that a pattern that has more small dense LDL particles, called Pattern B, equates to a higher risk factor for
coronary heart disease (CHD) than does a pattern with
more of the larger and less-dense LDL particles (Pattern
A). This is thought to be because the smaller particles are
1

3 MEDICAL RELEVANCE - ATHEROSCLEROSIS

more easily able to penetrate the endothelium. Pattern

I, for intermediate, indicates that most LDL particles are
very close in size to the normal gaps in the endothelium
(26 nm). According to one study, sizes 19.020.5 nm
were designated as pattern B and LDL sizes 20.622 nm
were designated as pattern A.[8]

classication).

When a cell requires additional cholesterol (beyond its

current internal HMGCoA production pathway), it synthesizes the necessary LDL receptors, and inserts them
into the plasma membrane. The LDL receptors diuse
freely until they associate with clathrin-coated pits. LDL
particles in the bloodstream bind to these extracellular
LDL receptors. The clathrin-coated pits then form vesicles that are endocytosed into the cell.

Keep in mind that LDL-C is not a measurement of actual LDL particles; LDL-C is only an estimate (not measured from the individuals blood sample) of how much
cholesterol is being transported by all LDL particles; either a smaller concentration of large particles or a high
concentration of small particles. Also keep in mind
that LDL particles carry many fat molecules (typically
3,000 to 6,000 fat molecules per LDL particle); this includes cholesterol, triglycerides, phospholipids and others. Thus even if the hundreds to thousands of cholesterol
molecules within an average LDL particle were measured, this does not reect the other fat molecules or even
the number of LDL particles.

LDL particles pose a risk for cardiovascular disease when

they invade the endothelium and become oxidized, since
the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL particles, chiey stimulated
Some in the medical community have suggested the cor- by presence of necrotic cell debries[13] and free radicals
respondence between Pattern B and CHD is stronger than in the endothelium.
the correspondence between the LDL number measured
in the standard lipid prole test. Tests to measure these
LDL subtype patterns have been more expensive and not 3.1 Role in the innate immune system
widely available, so the common lipid prole test is used
more often.[9]
LDL lipoproteins interfere with the quorum sensing
There has also been noted a correspondence between system that upregulates genes required for invasive
higher triglyceride levels and higher levels of smaller, Staphylococcus aureus infection. The mechanism of andenser LDL particles and alternately lower triglyceride tagonism entails binding Apolipoprotein B, to a S. aureus
levels and higher levels of the larger, less dense (a.k.a. autoinducer pheromone, preventing signaling through its
receptor. Mice decient in apolipoprotein B are more
buoyant) LDL.[10][11]
susceptible to invasive bacterial infection.[14]
With continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass
analysis assay methods, including NMR spectroscopy,[12] 3.2 Lowering LDL-C
research studies have continued to show a stronger correlation between human clinically obvious cardiovascuThe mevalonate pathway serves as the basis for the
lar events and quantitatively measured particle concenbiosynthesis of many molecules, including cholesterol.
trations.
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component
and performs the rst of 37 steps within the cholesterol
2.3 Transport into the cell
production pathway, and present in every animal cell.

After the clathrin coat is shed, the vesicles deliver the

LDL and their receptors to early endosomes, onto late
endosomes to lysosomes. Here the cholesterol esters in
the LDL are hydrolysed. The LDL receptors are recycled back to the plasma membrane.

3.2.1 Pharmaceutical

Medical relevance - Atherosclerosis

LDL particles are formed as VLDL lipoproteins lose

triglyceride through the action of lipoprotein lipase (LPL)
and they become smaller and denser (i.e. fewer fat
molecules with same protein transport shell), containing
a higher proportion of cholesterol esters.[13]
A hereditary form of high LDL is familial hypercholesterolemia (FH). Increased LDL is termed
hyperlipoproteinemia type II (after the dated Fredrickson

Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells,
the rate-limiting step of cholesterol synthesis. To
compensate for the decreased cholesterol availability, synthesis of hepatic LDL receptors is increased,
resulting in an increased clearance of LDL particles
from the blood.
Ezetimibe reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations
when combined with statins.[18]

3.3

Importance of antioxidants

PCSK9 inhibitors, in phase 3 clinical trials, by several companies, appear to be far more eective for
LDL reduction than the statins, even statins at high
dose.
Niacin (B3 ), lowers LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reducing
triglyceride synthesis and VLDL secretion through a
receptor HM74[19] and HM74A or GPR109A.[20]
Several CETP inhibitors have been researched to
improve HDL concentrations, but so far, despite
dramatically increasing HDL-C, have not had a consistent track record in reducing atherosclerosis disease events. Some have increased mortality rates
compared with placebo.

3
activity.[26] While glucagon production is stimulated
by dietary protein ingestion, insulin production is
stimulated by dietary carbohydrate. The rise of insulin is, in general, determined by the digestion of
carbohydrates into glucose and subsequent increase
in serum glucose levels. In non-diabetics, glucagon
levels are very low when insulin levels are high; however, those who have become diabetic no longer suppress glucagon output after eating.
A ketogenic diet may have similar response to taking
niacin (lowered LDL and increased HDL) through
beta-hydroxybutyrate, a ketone body, coupling the
niacin receptor (HM74A).[20]
Lowering the blood lipid concentration of
triglycerides helps lower the concentration of
small LDL particles, because fatty-acid rich VLDL
particles convert in the bloodstream into small
dense LDL particles.

Clobrate is eective at lowering cholesterol levels,

but has been associated with signicantly increased
cancer and stroke mortality, despite lowered cholesterol levels.[21] Other, more recently developed and
tested brates, e.g. fenobric acid[22] have had a better track record and are primarily promoted for low3.2.2 Lifestyle
ering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other
The most eective approach has been minimizing
strategies.
fat stores located inside the abdominal cavity (visceral body fat) in addition to minimizing total body
Some Tocotrienols, especially delta- and gammafat. Visceral fat, which is more metabolically actocotrienols, are being promoted as statin alternative than subcutaneous fat, has been found to protive non-prescription agents to treat high cholesduce many enzymatic signals, e.g. resistin, which interol, having been shown in vitro to have an eect.
crease insulin resistance and circulating VLDL parIn particular, gamma-tocotrienol appears to be anticle concentrations, thus both increasing LDL partiother HMG-CoA reductase inhibitor, and can recle concentrations and accelerating the development
duce cholesterol production.[23] As with statins, this
of Diabetes Mellitus.
decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key is A 2004 pilot study of Garcinia Cambogia saw that
sue is how benets and complications of such agents
test subjects who took Garcinia Cambogia reduced
compare with statinsmolecular tools that have
their level of LDL cholesterol by an average of
been analyzed in large numbers of human research
14%, whilst the control group saw only a 0.8%
and clinical trials since the mid-1970s.
reduction.[27] The main ingredient in Garcinia Cambogia and other tropical fruits is Hydroxycitric acid.
Phytosterols are widely recognized as having a
proven LDL cholesterol lowering ecacy.[24] Current supplemental guidelines recommend doses of 3.3 Importance of antioxidants
phytosterols in the 1.6-3.0 grams per day range
(Health Canada, EFSA, ATP III,FDA) with a re- Because LDL particles appear harmless until they are
cent meta-analysis demonstrating an 8.8% reduction within the blood vessel walls and oxidized by free
in LDL-cholesterol at a mean dose of 2.15 gram radicals,[28] it is postulated that ingesting antioxidants
per day.[25] However, plant sterols and stanols, if and minimizing free radical exposure may reduce LDLs
absorbed (intestinal cells generally block), greatly contribution to atherosclerosis, though results are not
accelerate progression of atherosclerosis more than conclusive.[29][30] Studies have reported the benets of
cholesterol delivered into the arterial walls by green tea in helping to reduce LDL; some studies have
lipoprotein particles.
focused on the antioxidant qualities of the unfermented
green tea leaves,[31] others looked at green-tea com Insulin induces HMG-CoA reductase activity, pounds called catechins which are thought to decrease
whereas glucagon diminishes HMG-CoA reductase cholesterol absorption in the gut.[32]

4 ESTIMATION OF LDL PARTICLES VIA CHOLESTEROL CONTENT

Estimation of LDL particles via

cholesterol content

clinical outcomes, such as diabetes mellitus, obesity and

smoking, lose most of their predictive accuracy.

Chemical measures of lipid concentration have long been

the most-used clinical measurement, not because they 4.1 Normal ranges
have the best correlation with individual outcome, but
because these lab methods are less expensive and more In the USA, the American Heart Association, NIH,
and NCEP provide a set of guidelines for fasting LDLwidely available.
Cholesterol levels, estimated or measured, and risk for
The lipid prole does not measure LDL particles. It heart disease. As of about 2005, these guidelines
only estimates them using the Friedewald equation[11][33] were:[36][37][38]
by subtracting the amount of cholesterol associated with
other particles, such as HDL and VLDL, assuming a pro- Over time, with more clinical research, these recommended levels keep being reduced because LDL reduclonged fasting state, etc.:
tion, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in
L C H kT
one large double blind, randomized clinical trial of men
where H is HDL cholesterol, L is LDL choleswith hypercholesterolemia;[39] far more eective than
terol, C is total cholesterol, T are triglycerides,
coronary angioplasty/stenting or bypass surgery[40]
and k is 0.20 if the quantities are measured in
For instance, for people with known atherosclerosis dismg/dl and 0.45 if in mmol/l.
eases, the 2004 updated American Heart Association,
There are limitations to this method, most notably that NIH and NCEP recommendations are for LDL levels to
samples must be obtained after a 12 to 14 h fast and be lowered to less than 70 mg/dL, unspecied how much
that LDL-C cannot be calculated if plasma triglyceride lower. This low level of less than 70 mg/dL was recis >4.52 mmol/L (400 mg/dL). Even at triglyceride ommended for primary prevention of 'very-high risk palevels 2.5 to 4.5 mmol/L, this formula is considered tients and in secondary prevention as a 'reasonable furinaccurate.[34] If both total cholesterol and triglyceride ther reduction'. Lack of evidence for such a recommenlevels are elevated then a modied formula, with quan- dation is discussed in an article in the Annals of internal
medicine.[41] It should also be noted that statin drugs intities in mg/dl, may be used
volved in such clinical trials have numerous physiological
eects beyond simply the reduction of LDL levels.
L = C H 0.16T
It has been estimated from the results of multiple huThis formula provides an approximation with fair accu- man pharmacologic LDL lowering trials that LDL should
racy for most people, assuming the blood was drawn after be lowered to about 50 to reduce cardiovascular event
fasting for about 14 hours or longer, but does not reveal rates to near zero. For reference, from longitudinal popthe actual LDL particle concentration because the per- ulation studies following progression of atherosclerosisrelated behaviors from early childhood into adulthood, it
centage of fat molecules within the LDL particles which
has been discovered that the usual LDL in childhood, beare cholesterol varies, as much as 8:1 variation.
fore the development of fatty streaks, is about 35 mg/dL.
However, the concentration of LDL particles, and to a However, all the above values refer to chemical measures
lesser extent their size, has a stronger and consistent cor- of lipid/cholesterol concentration within LDL, not mearelation with individual clinical outcome than the amount sured Low Density Lipoprotein concentrations, the accuof cholesterol within LDL particles, even if the LDL-C rate approach.
estimation is approximately correct. There is increasing
evidence and recognition of the value of more targeted The feasibility of these gures has been questioned by
and accurate measurements of LDL particles. Specif- sceptics, claiming that many members of the AHA and
ically, LDL particle number (concentration), and to a NIH are heavily associated with pharmaceutical compalesser extent size, have shown slightly stronger correla- nies giving them bias towards lowering cholesterol levels
tions with atherosclerotic progression and cardiovascu- and such guidelines giving rise to increased use of choleslar events than obtained using chemical measures of the terol lowering medicine such as statins.
amount of cholesterol carried by the LDL particles.[35] A study was conducted measuring the eects of guideIt is possible that the LDL cholesterol concentration can line changes on LDL cholesterol reporting and control
be low, yet LDL particle number high and cardiovascular for diabetes visits in the US from 1995 to 2004. It was
events rates are high. Correspondingly, it is possible that found that although LDL cholesterol reporting and conLDL cholesterol concentration can be relatively high, yet trol for diabetes and coronary heart disease visits imLDL particle number low and cardiovascular events are proved continuously between 1995 and 2004, neither the
also low. If LDL particle concentration is used to pre- 1998 ADA guidelines nor the 2001 ATP III guidelines
dict cardiovascular events, many other correlates of these increased LDL cholesterol control for diabetes relative to

5
coronary heart disease.[42]

the higher groups. Multiple other measures, including

Moreover, there are publications regarding the risks of particle sizes, small LDL particle concentrations, total
and large HDL particle concentrations, along with estilow-LDL cholesterol too.
mations of insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma
data with the estimation methods discussed above) are
5 Direct measurement of LDL par- also routinely provided.
[43]

ticle concentrations
There are several competing methods for measurement
of lipoprotein particle concentrations and size. The evidence is that the NMR methodology (developed, automated & greatly reduced in costs while improving accuracy as pioneered by Jim Otvos and associates) results
in a 22-25% reduction in cardiovascular events within
just a single year,[44] contrary to the longstanding claims
by many in the medical industry that the superiority
over existing methods was weak, even by statements of
some proponents.[45] Direct LDL particle measurement
by NMR was mentioned by the ADA and ACC, in a 28
March 2008 joint consensus statement,[46] as having advantages for predicting individual risk of atherosclerosis
disease events, but the statement noted that the test is
less widely available (single vendor which accepts sample
from world-wide), is more expensive (about $80.00 US
without insurance coverage) and it is "...unclear whether
LDL particle size measurements add value to measurement of LDL particle concentration, an issue which LipoScience consultants also tend to agree with (yet also
has little to do with the value of measuring LDL particles
vs. ApoB vs. cholesterol). Since the later 1990s, because of the development of NMR measurements, it has
been possible to clinically measure lipoprotein particles
at lower cost [under $100 US (including shipping) & deceasing; versus the previous costs of >$400 to >$5,000]
and higher accuracy. There are also other (less expensive) homogeneous assays for LDL, however most only
estimate LDL.
Using NMR, as pioneered by researcher Jim Otvos and
the North Carolina State University academic research
spino company LipoScience, the total LDL particle
concentrations, in nmol/L plasma, are typically subdivided by percentiles referenced to the 5,382 men and
women, not on any lipid medications, who are participating in the MESA trial.[47]

6 See also
Catechin
Cholesterol
Lysosomal acid lipase deciency
Cholesteryl ester storage disease
Coenzyme Q10
Flavonoid
Glutathione
Health eects of tea
High density lipoprotein
LDL receptor
Lipid prole
Lipoprotein(a)
Lipoprotein-X
Melatonin
Polyphenol antioxidant
Saturated fat
Stanol ester
Sterol ester
Triglyceride
Vitamin A
Vitamin C

5.1

Optimal ranges

The LDL particle concentrations are typically categorized by percentiles, <20%, 2050%, 50th80th%, 80th
95% and >95% groups of the people participating and being tracked in the MESA trial, a medical research study
sponsored by the United States National Heart, Lung, and
Blood Institute.
The lowest incidence of atherosclerotic events over time
occurs within the <20% group, with increased rates for

Vitamin E

7 Footnotes
[1] Dashti M, Kulik W, Hoek F, Veerman EC, Peppelenbosch MP, Rezaee F. (2011). A phospholipidomic analysis of all dened human plasma lipoproteins.. Sci Rep.
1 (139). doi:10.1038/srep00139. PMC 3216620. PMID
22355656.

[2] Dashty M, Motazacker MM, Levels J, de Vries M, Mahmoudi M, Peppelenbosch MP, Rezaee F. (2014). Proteome of human plasma very low-density lipoprotein and
low-density lipoprotein exhibits a link with coagulation
and lipid metabolism.. Thromb Haemost. 23 (111): 518
530. 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 Whats
Good?

7 FOOTNOTES

[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 Eectiveness Review Project
(March 2013), Evaluating statin drugs to treat High
Cholesterol and Heart Disease: Comparing Eectiveness,
Safety, and Price, Best Buy Drugs (Consumer Reports):
9, retrieved 27 March 2013, which cites
United States Department of Health and Human
Services; National Heart, Lung, and Blood Institute;
National Institutes of Health (June 2005). NHLBI,
High Blood Cholesterol: What You Need to Know.
nhlbi.nih.gov. Retrieved 27 March 2013.

[5] John D. Brunzell, MD, FACP, Michael Davidson, MD,

FACC, Curt D. Furberg, MD, PhD, Ronald B. Goldberg, MD, Barbara V. Howard, PhD, James H. Stein, MD,
FACC, FACP and Joseph L. Witztum, MD Lipoprotein
Management in Patients With Cardiometabolic Risk, J
Am Coll Cardiol, 2008; 51:1512-1524.

[18]

[6] Segrest JP, Jones MK, De Loof H, Dashti N (September

2001). Structure of apolipoprotein B-100 in low density
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[19] Meyers CD, Kamanna VS, Kashyap ML (December

2004). Niacin therapy in atherosclerosis. Current Opinion in Lipidology 15 (6): 65965. doi:10.1097/00041433200412000-00006. PMID 15529025.

[7] Kumar V, Butcher SJ, Katrina O,Engelhardt P,Heikkonen

J, Kaski K, Ala-Korpela M, Kovanen PT. (May 2011).
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doi:10.1371/journal.pone.0018841.
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[20] Soudijn W, van Wijngaarden I, Ijzerman AP (May

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4960280510/pdf
[9] http://www.msnbc.msn.com/id/
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bad-cholesterol-its-not-what-you-think/#.T4Gkub_
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[21] WHO cooperative trial on primary prevention of ischemic heart disease with clobrate to lower serum
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[22] http://www.rxabbott.com/pdf/trilipix_pi.pdf
[23] Song, B.L.; DeBose-Boyd, R.A. (2006).
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[24] European Food Safety Authority, Journal (2010).
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related to plant sterols and plant stanols and maintenance
of normal blood cholesterol concentrations.
[25] Demonty, I; Ras, RT, van der Knaap, HC, Duchateau,
GS, Meijer, L, Zock, PL, Geleijnse, JM, Trautwein,
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[26] Regulation of Cholesterol Synthesis

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

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

[14] Peterson MM, Mack JL, Hall PR, et al. (December 2008).
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[41] Narrative Review: Lack of Evidence for Recommended
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[42] Wang, Y Richard; G Caleb Alexander and David O

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[43] Low serum LDL cholesterol levels and the risk of fever,
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[46]
[47]

8 External links
Fat (LDL) Degradation: PMAP The Proteolysis
Map-animation
Adult Treatment Panel III Full Report
ATP III Update 2004
O'Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R (June 2004). Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and
physiologically normal. Journal of the American College of Cardiology 43 (11): 21426.
doi:10.1016/j.jacc.2004.03.046. PMID 15172426.

9 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

Text and image sources, contributors, and licenses

9.1

Text

Low-density lipoprotein Source: http://en.wikipedia.org/wiki/Low-density%20lipoprotein?oldid=643831008 Contributors: Kpjas, Bryan

Derksen, Andre Engels, Rgamble, Mbmanie, Gabbe, Milksh, Tristanb, Charles Matthews, Maximus Rex, Joy, Jeq, PuzzletChung, Robbot, Stewartadcock, Mr-Natural-Health, Kd4ttc, Fuelbottle, Diberri, Giftlite, DocWatson42, Ksheka, Everyking, Jfdwol, Bobblewik,
Erich gasboy, Alexf, Beland, PFHLai, Elektron, Ukexpat, Abdull, Rich Farmbrough, Guanabot, Cacycle, NickVeys, MAlvis, Sietse
Snel, Smalljim, Davidruben, Richi, Arcadian, Sriram sh, KBi, Unused000701, Googie man, Nereocystis, Arthena, Shoey, Boyd Steere,
Gene Nygaard, Jigsaw, Pol098, Tabletop, BorisTM, Koolkao, Rjwilmsi, Bhadani, Hathawayc, Dvdmon, FlaBot, Jeanpol, Gkelly, Mhking, Roboto de Ajvol, Raelx, Chris Capoccia, Draeco, Bmdavll, Stellis, Dfgriggs, Davidpatrick, Eurosong, Johnsleonard, StuRat, Mateo
LeFou, 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, Coee2theorems, Magioladitis,
VoABot II, Karkaputto, Peaceandlove666, WhatamIdoing, Allstarecho, Nono64, AgarwalSumeet, Nbauman, Xris0, Mike.lifeguard, Funandtrvl, 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 Should
Not Be, Mild Bill Hiccup, Doseiai2, Edenatude, Auntof6, Dlf723, Pandnh4, Razorame, 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, RegulatorRectier,
Ls62206, Wikipism, FrescoBot, Quicktriggernger, D'ohBot, Citation bot 1, Pinethicket, Codwiki, Mjs1991, Land90, Gamingmaster125,
Demiallylovato, Tbhotch, Mean as custard, RjwilmsiBot, EmausBot, Immunize, GoingBatty, We hope, 22Kartika, Wikimk, Amitbalani,
Erianna, JeanneMish, Mac John Concord, ClueBot NG, Frietjes, JohnnyRed2011, JennH123, Helpful Pixie Bot, BG19bot, SharkinthePool,
Frze, Monika md, JohnCAPSIC, Eman2129, Cquang, Yeokesh, Theunpwnable, Saxyjbik06, Roland Stocker, Aseyeseeit, Pinkrabbit23,
Cholesterolverlagen, Alangomes429, Arripay, Manul, Anrnusna, BIOHIGH, Monkbot, Shanman75, Amjedziadah, MarcusVorenus, Marketingomegalife and Anonymous: 208

9.2

Images

File:Edit-clear.svg Source: http://upload.wikimedia.org/wikipedia/en/f/f2/Edit-clear.svg License: Public domain Contributors: The

Tango! Desktop Project. Original artist:
The people from the Tango! project. And according to the meta-data in the le, specically: Andreas Nilsson, and Jakub Steiner (although
minimally).
File:Question_book-new.svg Source: http://upload.wikimedia.org/wikipedia/en/9/99/Question_book-new.svg License: Cc-by-sa-3.0
Contributors:
Created from scratch in Adobe Illustrator. Based on Image:Question book.png created by User:Equazcion Original artist:
Tkgd2007

9.3

Content license

Creative Commons Attribution-Share Alike 3.0