Editing Low-density lipoprotein

{{Short description|One of the five major groups of lipoprotein}}
{{Redirect|LDL}}
[[File:Atheroma.jpg|thumb|256x256px|LDL has been associated with the progression of atherosclerosis and blockage of the artery lumen, because it can carry cholesterol into smaller vessels. But LDL is also essential for carrying lipids that keep the human body alive, including in those small vessels.]]

'''Low-density lipoprotein''' ('''LDL''') is one of the five major groups of [[lipoprotein]] that transport all [[fat]] molecules around the body in extracellular water.<ref>{{Cite web |title=LDL and HDL: Bad and Good Cholesterol |url=https://www.cdc.gov/cholesterol/ldl_hdl.htm |access-date=11 September 2017 |website=Centers for Disease Control and Prevention |publisher=CDC |ref=cdc-hdl-ldl}}</ref> These groups, from least dense to most dense, are [[chylomicron]]s (aka [[ULDL]] by the overall density naming convention), [[very low-density lipoprotein]] (VLDL), [[intermediate-density lipoprotein]] (IDL), low-density lipoprotein (LDL) and [[high-density lipoprotein]] (HDL). LDL delivers fat molecules to [[Cell (biology)|cells]]. LDL has been associated with the progression of [[atherosclerosis]].

==Overview==
Lipoproteins transfer [[lipid]]s ([[fat]]s) around the body in the [[extracellular fluid]], making fats available to body cells for [[receptor-mediated endocytosis]].<ref>{{cite journal |last1=Dashti |first1=Monireh |last2=Kulik |first2=Willem |last3=Hoek |first3=Frans |last4=Veerman |first4=Enno C. |last5=Peppelenbosch |first5=Maikel P. |last6=Rezaee |first6=Farhad |title=A Phospholipidomic Analysis of All Defined Human Plasma Lipoproteins |journal=Scientific Reports |date=7 November 2011 |volume=1 |issue=1 |page=139 |doi=10.1038/srep00139 |bibcode=2011NatSR...1..139D |pmc=3216620 |pmid=22355656 }}</ref><ref>{{cite journal |last1=Dashty |first1=Monireh |last2=Motazacker |first2=Mohammad M. |last3=Levels |first3=Johannes |last4=Vries |first4=Marcel de |last5=Mahmoudi |first5=Morteza |last6=Peppelenbosch |first6=Maikel P. |last7=Rezaee |first7=Farhad |title=Proteome of human plasma very low-density lipoprotein and low-density lipoprotein exhibits a link with coagulation and lipid metabolism |journal=Thrombosis and Haemostasis |date=2014 |volume=112 |issue=3 |pages=518–530 |doi=10.1160/TH13-02-0178 |pmid=24500811 }}</ref> Lipoproteins are complex particles composed of multiple [[protein]]s, typically 80–100 proteins per particle (organized by a single [[apolipoprotein B]] for LDL and the larger particles). A single LDL particle is about 22–27.5 nanometers in diameter, typically transporting 3,000 to 6,000 fat molecules per particle and varying in size according to the number and mix of fat molecules contained within.<ref name="Segrest JP, Jones MK, De Loof H, Dashti N 1346–67">{{Cite journal |vauthors=Segrest JP, Jones MK, De Loof H, Dashti N |date=September 2001 |title=Structure of apolipoprotein B-100 in low density lipoproteins |journal=Journal of Lipid Research |volume=42 |issue=9 |pages=1346–67 |doi=10.1016/S0022-2275(20)30267-4 |pmid=11518754 |doi-access=free}}</ref> The lipids carried include all fat molecules with [[cholesterol]], [[phospholipids]], and [[triglycerides]] dominant; amounts of each vary considerably.<ref>{{Cite book |last=Sira |first=Elevina E. Pérez |url=https://books.google.com/books?id=MIROEAAAQBAJ&pg=PA208 |title=Foods for Special Dietary Regimens |date=2021-10-05 |publisher=Bentham Science Publishers |isbn=978-981-4998-07-9 |language=en}}</ref>

A good clinical interpretation of blood lipid levels is that high LDL, in combination with a low amount of HDL, is associated with an increased risk of [[cardiovascular diseases]].<ref name="Carson-AHA ">{{Cite journal |last1=Carson |first1=Jo Ann S. |last2=Lichtenstein |first2=Alice H. |last3=Anderson |first3=Cheryl A.M. |last4=Appel |first4=Lawrence J. |last5=Kris-Etherton |first5=Penny M. |last6=Meyer |first6=Katie A. |last7=Petersen |first7=Kristina |last8=Polonsky |first8=Tamar |last9=Van Horn |first9=Linda |date=2020-01-21 |title=Dietary cholesterol and cardiovascular risk: A science advisory from the American Heart Association |journal=Circulation |volume=141 |issue=3 |pages=e39–e53 |doi=10.1161/cir.0000000000000743 |pmid=31838890 |doi-access=free}}</ref>

==Biochemistry==

===Structure===
Each native LDL particle enables emulsification, i.e. surrounding the 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 ([[Apolipoprotein B|Apo B-100]], a protein that has 4536 [[amino acid]] residues and a mass of 514 [[Atomic mass unit|kDa]]), along with 80 to 100 additional ancillary proteins. Each LDL has a highly hydrophobic core consisting of [[Polyunsaturated fat|polyunsaturated fatty acid]] known as [[Linoleic acid|linoleate]] and hundreds to thousands (about 1500 commonly cited as an average) of [[ester]]ified and unesterified cholesterol molecules. This core also carries varying numbers of triglycerides and other fats and is surrounded by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100. LDL particles are approximately 22&nbsp;nm (0.00000087&nbsp;in.) to 27.5&nbsp;nm in diameter and have a mass of about 3 million daltons.<ref>{{Cite journal |last=Campos, Hannia |date=1992 |title=LDL Particle Size Distribution |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=12 |issue=12 |pages=1410–1419 |doi=10.1161/01.ATV.12.12.1410 |pmid=1450174 |doi-access=free}}</ref> Since LDL particles contain a variable and changing number of fatty acid molecules, there is a distribution of LDL particle mass and size.<ref name="Segrest JP, Jones MK, De Loof H, Dashti N 1346–67" /> Determining the structure of LDL has been difficult for biochemists because of its heterogeneous structure. However, the structure of LDL at human body temperature in native condition, with a resolution of about 16 [[Angstroms]] using [[cryogenic electron microscopy]], has been described in 2011.<ref>{{Cite journal |vauthors=Kumar V, Butcher SJ, Katrina O, Engelhardt P, Heikkonen J, Kaski K, Ala-Korpela M, Kovanen PT |date=May 2011 |title=Three-Dimensional cryoEM Reconstruction of Native LDL Particles to 16Å Resolution at Physiological Body Temperature |journal=PLOS ONE |volume=6 |issue=5 |pages=e18841 |bibcode=2011PLoSO...618841K |doi=10.1371/journal.pone.0018841 |pmc=3090388 |pmid=21573056 |doi-access=free}}</ref>

==Physiology==
LDL particles are formed when triglycerides are removed from VLDL by the [[lipoprotein lipase]] enzyme (LPL), and they become smaller and denser (i.e., fewer fat molecules with the same protein transport shell), containing a higher proportion of cholesterol esters.<ref>{{cite book |last1=Pirahanchi |first1=Yasaman |last2=Sinawe |first2=Hadeer |last3=Dimri |first3=Manjari |chapter=Biochemistry, LDL Cholesterol |date=8 August 2023 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK519561/ |title=StatPearls |publisher=StatPearls |pmid=30137845 }}</ref><ref>{{Cite journal |last1=Sun |first1=Hung-Yu |last2=Lin |first2=Chun-Chieh |last3=Lee |first3=Jin-Ching |last4=Wang |first4=Shainn-Wei |last5=Cheng |first5=Pin-Nan |last6=Wu |first6=I.-Chin |last7=Chang |first7=Ting-Tsung |last8=Lai |first8=Ming-Derg |last9=Shieh |first9=Dar-Bin |last10=Young |first10=Kung-Chia |date=July 3, 2013 |title=Very low-density lipoprotein/lipo-viro particles reverse lipoprotein lipase-mediated inhibition of hepatitis C virus infection via apolipoprotein C-III |journal=Gut |volume=62 |issue=8 |pages=1193–1203 |doi=10.1136/gutjnl-2011-301798 |pmid=22689516 }}</ref>

===Transport into the cell===
When a cell requires more cholesterol than its [[HMG-CoA reductase|HMG-CoA]] pathway can produce, it synthesizes the necessary [[LDL receptor]]s as well as [[PCSK9]], a [[proprotein convertase]] that marks the LDL receptor for degradation.<ref>{{cite journal |last1=Zhang |first1=Da-Wei |last2=Garuti |first2=Rita |last3=Tang |first3=Wan-Jin |last4=Cohen |first4=Jonathan C. |last5=Hobbs |first5=Helen H. |title=Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor |journal=Proceedings of the National Academy of Sciences |date=2 September 2008 |volume=105 |issue=35 |pages=13045–13050 |doi=10.1073/pnas.0806312105 |bibcode=2008PNAS..10513045Z |pmc=2526098 |pmid=18753623 |doi-access=free}}</ref> LDL receptors are inserted into the plasma membrane and diffuse freely until they associate with [[clathrin]]-coated pits. When LDL receptors bind LDL particles in the bloodstream, the clathrin-coated pits are endocytosed into the cell.{{cn|date=November 2024}}

Vesicles containing LDL receptors bound to LDL are delivered to the [[endosome]]. In the presence of low [[pH]], such as that found in the endosome, LDL receptors undergo a conformation change, releasing LDL. LDL is then shipped to the [[lysosome]], where [[cholesterol ester]]s in the LDL are [[Hydrolysis|hydrolysed]]. LDL receptors are typically returned to the plasma membrane, where they repeat this cycle. If LDL receptors bind to PCSK9, however, transport of LDL receptors is redirected to the lysosome, where they are degraded.<ref>{{Cite journal |vauthors=Santulli G, Jankauskas SS, Gambardella J |date=May 2021 |title=Inclisiran: a new milestone on the PCSK9 road to tackle cardiovascular risk |journal=Eur Heart J Cardiovasc Pharmacother |volume=7 |issue=3 |pages=e11–e12 |doi=10.1093/ehjcvp/pvab014 |pmid=33655296 |doi-access=free}}</ref>

===Role in the innate immune system===
LDL interferes with the [[quorum sensing]] system that upregulates genes required for invasive ''[[Staphylococcus aureus]]'' infection. The mechanism of antagonism entails binding apolipoprotein B to a ''S. aureus'' [[autoinducer]] pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.<ref name="Apolipoprotein B Is an innate barrier against invasive Staphylococcus aureus infection">{{Cite journal |vauthors=Peterson MM, Mack JL, Hall PR, et al |date=December 2008 |title=Apolipoprotein B Is an innate barrier against invasive Staphylococcus aureus infection |journal=Cell Host & Microbe |volume=4 |issue=6 |pages=555–66 |doi=10.1016/j.chom.2008.10.001 |pmc=2639768 |pmid=19064256}}</ref>

===LDL size patterns===
LDL can be grouped based on its size: large low-density LDL particles are described as ''pattern A'', and small high-density ("small dense") LDL particles are ''pattern B''.<ref>{{Cite web |date=2022-07-18 |title=When it comes to LDL, size matters |url=https://gethlth.com/when-it-comes-to-ldl-size-matters/ |access-date=2022-08-04 |website=HLTH Code |language=en-US}}</ref> ''Pattern B'' has been associated by some with a higher risk for [[Coronary artery disease]].<ref name="pmid28572872" />{{rp|1–10}} This is thought to be because the smaller particles are more easily able to penetrate the [[endothelium]] of [[artery|arterial walls]]. ''Pattern I'', or ''intermediate'', indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26&nbsp;nm). According to one study, sizes 19.0–20.5&nbsp;nm were designated as pattern B and LDL sizes 20.6–22&nbsp;nm were designated as pattern A.<ref>{{Cite journal |last1=Bhalodkar |first1=Narendra C. |last2=Blum |first2=Steve |last3=Rana |first3=Thakor |last4=Kitchappa |first4=Radha |last5=Bhalodkar |first5=Ami N. |last6=Enas |first6=Enas A. |date=1 May 2005 |title=Comparison of high-density and low-density lipoprotein cholesterol subclasses and sizes in Asian Indian women with Caucasian women from the Framingham offspring study |journal=Clin Cardiol |volume=28 |issue=5 |pages=247–251 |doi=10.1002/clc.4960280510 |pmc=6654695 |pmid=15971461}}</ref>

Some evidence suggests the correlation between pattern B and coronary artery disease is stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the standard lipid profile test is used more often.<ref name="pmid28572872">{{Cite journal |vauthors=Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN |year=2017 |title=Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases |journal=[[List of Hindawi academic journals#O|Oxidative Medicine and Cellular Longevity]] |volume=2017 |issue=10 |pages=1273042 |doi=10.1155/2017/1273042 |pmc=5441126 |pmid=28572872 |doi-access=free}}</ref>

There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense ("buoyant") LDL.<ref name="pmid12417832">{{Cite journal |vauthors=Superko HR, Nejedly M, Garrett B |year=2002 |title=Small LDL and its clinical importance as a new CAD risk factor: a female case study |journal=Progress in Cardiovascular Nursing |volume=17 |issue=4 |pages=167–73 |doi=10.1111/j.0889-7204.2002.01453.x |pmid=12417832}}</ref><ref name="Warnick" />

With continued research, decreasing cost, greater availability, and wider acceptance of other ''lipoprotein subclass analysis'' assay methods, including [[NMR spectroscopy]], research studies have shown a stronger correlation between clinically evident human cardiovascular events and quantitatively measured particle concentrations.<ref>{{Cite journal |last=Otvos J |date=June 1999 |title=Measurement of triglyceride-rich lipoproteins by nuclear magnetic resonance spectroscopy |journal=Clin Cardiol |volume=22 |issue=6 Suppl |pages=II21–7 |doi=10.1002/clc.4960221405 |pmc=6655988 |pmid=10376193}}</ref>

===Oxidized LDL===
Oxidized LDL (oxLDL) is a general term for LDL particles with oxidatively modified structural components. As a result, from [[free radical]] attack, both lipid and protein parts of LDL can be oxidized in the vascular wall. Besides the oxidative reactions in the vascular wall, oxidized lipids in LDL can also be derived from oxidized dietary lipids.<ref>{{Cite journal |last1=Staprans |first1=I. |last2=Rapp |first2=J. H. |last3=Pan |first3=X. M. |last4=Feingold |first4=K. R. |year=1996 |title=Oxidized lipids in the diet are incorporated by the liver into very low density lipoprotein in rats |journal=Journal of Lipid Research |volume=37 |issue=2 |pages=420–30 |doi=10.1016/S0022-2275(20)37628-8 |pmid=9026539 |doi-access=free}}</ref><ref name="Ahotupa">{{Cite journal |last=Ahotupa |first=Markku |year=2017 |title=Oxidized lipoprotein lipids and atherosclerosis |journal=Free Radical Research |volume=51 |issue=4 |pages=439–447 |doi=10.1080/10715762.2017.1319944 |pmid=28412863 |url=https://figshare.com/articles/journal_contribution/4986497 }}</ref> Oxidized LDL is known to associate with the development of [[atherosclerosis]], and it is therefore widely studied as a potential risk factor of [[cardiovascular diseases]].<ref name="Stocker">{{Cite journal |last1=Stocker |first1=Roland |last2=Keaney |first2=John F. |year=2004 |title=Role of Oxidative Modifications in Atherosclerosis |journal=Physiological Reviews |volume=84 |issue=4 |pages=1381–1478 |doi=10.1152/physrev.00047.2003 |pmid=15383655}}</ref> Atherogenicity of oxidized LDL has been explained by lack of recognition of oxidation-modified LDL structures by the LDL receptors, preventing the normal metabolism of LDL particles and leading eventually to the development of atherosclerotic plaques.<ref name=Stocker/> Of the lipid material contained in LDL, various lipid oxidation products are known as the ultimate atherogenic species.<ref>{{Cite journal |last=Birukov |first=K. G. |year=2006 |title=Oxidized lipids: The two faces of vascular inflammation |journal=Current Atherosclerosis Reports |volume=8 |issue=3 |pages=223–31 |doi=10.1007/s11883-006-0077-x |pmid=16640959 }}</ref> Acting as a transporter of these injurious molecules is another mechanism by which LDL can increase the risk of atherosclerosis.<ref name=Ahotupa/><ref>{{Cite journal |last1=Shao |first1=Baohai |last2=Heinecke |first2=Jay W. |year=2009 |title=HDL, lipid peroxidation, and atherosclerosis |journal=Journal of Lipid Research |volume=50 |issue=4 |pages=599–601 |doi=10.1194/jlr.E900001-JLR200 |pmc=2656652 |pmid=19141435 |doi-access=free}}</ref>

The [[LOX-1]] [[Scavenger receptor (immunology)|scavenge receptor]] does take up oxLDL, but the liver does not naturally express it.<ref>{{cite journal |last1=Wang |first1=Z |last2=Guo |first2=X |last3=Zhang |first3=Q |last4=Du |first4=G |last5=Zeng |first5=Z |last6=Zheng |first6=C |last7=Wei |first7=Y |title=Elimination of Ox-LDL through the liver inhibits advanced atherosclerotic plaque progression. |journal=International Journal of Medical Sciences |date=2021 |volume=18 |issue=16 |pages=3652–3664 |doi=10.7150/ijms.63065 |pmid=34790037|pmc=8579296 }}</ref> It is instead expressed by endothelial cells, platelets, macrophages, smooth muscle cells, and cardiomyocytes as an innate immune scavenge receptor. When activated, pro-inflammatory signals are generated in the cell, and damaging compounds are released as well. As a result, these cells are most sensitive to the effects of oxLDL.<ref>{{cite journal |last1=Barreto |first1=Joaquim |last2=Karathanasis |first2=Sotirios K. |last3=Remaley |first3=Alan |last4=Sposito |first4=Andrei C. |title=Role of LOX-1 (Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1) as a Cardiovascular Risk Predictor: Mechanistic Insight and Potential Clinical Use |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |date=January 2021 |volume=41 |issue=1 |pages=153–166 |doi=10.1161/ATVBAHA.120.315421|pmid=33176449 |pmc=9186447 }}</ref> [[SR-BI]] and [[CD36]], two class B scavenge receptors, also take up oxLDL into the macrophage.<ref>{{cite journal |last1=Sun |first1=B |last2=Boyanovsky |first2=BB |last3=Connelly |first3=MA |last4=Shridas |first4=P |last5=van der Westhuyzen |first5=DR |last6=Webb |first6=NR |title=Distinct mechanisms for OxLDL uptake and cellular trafficking by class B scavenger receptors CD36 and SR-BI. |journal=Journal of Lipid Research |date=December 2007 |volume=48 |issue=12 |pages=2560–70 |doi=10.1194/jlr.M700163-JLR200 |doi-access=free |pmid=17876058}}</ref>

Despite lower recognition efficacy by the LDLR, the liver does remove oxLDLs from the circulation. This is achieved by [[Kupffer cell]]s and [[liver sinusoidal endothelial cell]]s (LSECs). In LSECs, [[stabilin-1]] and [[stabilin-2]] mediate most of the uptake. Uptake of oxLDLs causes visible disruption to the structure of the LSEC in rats.<ref>{{cite journal |last1=Mao |first1=Hong |last2=Kruse |first2=Larissa D. |last3=Li |first3=Ruomei |last4=Oteiza |first4=Ana |last5=Struck |first5=Eike C. |last6=Schürstedt |first6=Jasmin |last7=Hübner |first7=Wolfgang |last8=Cogger |first8=Victoria C. |last9=Le Couteur |first9=David |last10=Wolfson |first10=Deanna L. |last11=Huser |first11=Thomas |last12=Ahluwalia |first12=Balpreet Singh |last13=Øie |first13=Cristina |last14=McCourt |first14=Peter A. G. |title=Impact of oxidized low-density lipoprotein on rat liver sinusoidal endothelial cell morphology and function |journal=npj Gut and Liver |date=23 October 2024 |volume=1 |issue=1 |doi=10.1038/s44355-024-00009-5|doi-access=free }}</ref> Doing the same also damages human LSEC cultures.<ref>{{cite journal |last1=Zhang |first1=Qi |last2=Liu |first2=Jing |last3=Liu |first3=Jia |last4=Huang |first4=Wenhui |last5=Tian |first5=Limin |last6=Quan |first6=Jinxing |last7=Wang |first7=Yunfang |last8=Niu |first8=Ruilan |title=oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1 |journal=Journal of Molecular Endocrinology |date=October 2014 |volume=53 |issue=2 |pages=281–293 |doi=10.1530/JME-14-0049|pmid=25057109 }}</ref>

=== Acetyl LDL ===
Acetyl LDL (acLDL) is a construct generated ''in vitro''. When scientists produced such a modified version of LDL, they found that a class of scavenge receptors, now called [[Scavenger_receptor_(immunology)#Class_A|SR-A]], can recognize them and take them up. Because scavenge receptors work much faster than the downregulated native LDL receptor of a macrophage, oxLDL and acLDL can both fill up a macrophage quickly, turning it into a [[foam cell]].<ref>{{cite book |last1=Miller |first1=Yury I. |last2=Tsimikas |first2=Sotirios |chapter=Lipoprotein Oxidation and Modification |title=Clinical Lipidology |date=2009 |pages=93–110 |doi=10.1016/B978-141605469-6.50012-3|isbn=978-1-4160-5469-6 }}</ref>

==Testing==
[[Blood tests]] commonly report LDL-C: the amount of cholesterol that is estimated to be contained with LDL particles, on average, using a formula, the [[Friedewald equation]]. In a clinical context, mathematically calculated estimates of LDL-C are commonly used to estimate how much low-density lipoproteins drive the progression of atherosclerosis. The problem with this approach is that LDL-C values are commonly discordant with both direct measurements of LDL particles and actual rates of atherosclerosis progression.{{cn|date=November 2024}}

Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and are available from only a couple of laboratories in the [[United States]]. In 2008, the [[American Diabetes Association|ADA]] and [[American College of Cardiology|ACC]] recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events.<ref>{{cite journal |last1=Brunzell |first1=John D. |last2=Davidson |first2=Michael |last3=Furberg |first3=Curt D. |last4=Goldberg |first4=Ronald B. |last5=Howard |first5=Barbara V. |last6=Stein |first6=James H. |last7=Witztum |first7=Joseph L. |title=Lipoprotein Management in Patients With Cardiometabolic Risk |journal=Journal of the American College of Cardiology |date=April 2008 |volume=51 |issue=15 |pages=1512–1524 |doi=10.1016/j.jacc.2008.02.034 |pmid=18402913 }}</ref>

===Estimation of LDL particles via cholesterol content===
Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcomes but because these lab methods are less expensive and more widely available.

The lipid profile does not measure LDL particles. It only estimates them using the Friedewald equation<ref name="Warnick">{{Cite journal |vauthors=Warnick GR, Knopp RH, Fitzpatrick V, Branson L |date=January 1990 |title=Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints |journal=Clinical Chemistry |volume=36 |issue=1 |pages=15–9 |doi=10.1093/clinchem/36.1.15 |pmid=2297909 |doi-access=free }}</ref><ref name="pmid4337382">{{Cite journal |vauthors=Friedewald WT, Levy RI, Fredrickson DS |date=June 1972 |title=Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge |journal=Clinical Chemistry |volume=18 |issue=6 |pages=499–502 |doi=10.1093/clinchem/18.6.499 |pmid=4337382 |doi-access=free }}</ref>
by subtracting the amount of cholesterol associated with other particles, such as [[High-density lipoprotein|HDL]] and VLDL, assuming a prolonged fasting state, etc.:
:<math>L \approx C - H - kT</math>
:where ''H'' is HDL cholesterol, ''L'' is LDL cholesterol, ''C'' is total cholesterol, ''T'' is triglycerides, and k is 0.20 if the quantities are measured in mg/dL and 0.45 in mmol/L.

There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52&nbsp;mmol/L (400&nbsp;mg/dL). Even at triglyceride levels of 2.5 to 4.5 mmol/L, this formula is considered inaccurate.<ref name="Sniderman">{{Cite journal |vauthors=Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J |date=October 2003 |title=Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula |journal=Clinical Biochemistry |volume=36 |issue=7 |pages=499–504 |doi=10.1016/S0009-9120(03)00117-6 |pmid=14563441}}</ref>  If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dL, may be used
:<math>L = C - H - 0.16T</math>

This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual LDL particle concentration because the percentage of fat molecules within the LDL particles, which are cholesterol, varies as much as 8:1 variation. There are several formulas published addressing the inaccuracy in LDL-C estimation.<ref>{{cite journal |last1=Anandaraja |first1=S. |last2=Narang |first2=R. |last3=Godeswar |first3=R. |last4=Laksmy |first4=R. |last5=Talwar |first5=K.K. |title=Low-density lipoprotein cholesterol estimation by a new formula in Indian population |journal=International Journal of Cardiology |date=June 2005 |volume=102 |issue=1 |pages=117–120 |doi=10.1016/j.ijcard.2004.05.009 |pmid=15939107 }}</ref><ref>{{Cite journal |last1=de Cordova |first1=Caio Mauricio Mendes |last2=de Cordova |first2=Mauricio Mendes |date=January 2013 |title=A new accurate, simple formula for LDL-cholesterol estimation based on directly measured blood lipids from a large cohort |journal=Annals of Clinical Biochemistry: International Journal of Laboratory Medicine |language=en |volume=50 |issue=1 |pages=13–19 |doi=10.1258/acb.2012.011259 |pmid=23108766 |doi-access=free}}</ref><ref>{{Cite journal |last1=Chen |first1=Yunqin |last2=Zhang |first2=Xiaojin |last3=Pan |first3=Baishen |last4=Jin |first4=Xuejuan |last5=Yao |first5=Haili |last6=Chen |first6=Bin |last7=Zou |first7=Yunzeng |last8=Ge |first8=Junbo |last9=Chen |first9=Haozhu |date=2010 |title=A modified formula for calculating low-density lipoprotein cholesterol values |journal=Lipids in Health and Disease |language=en |volume=9 |issue=1 |pages=52 |doi=10.1186/1476-511X-9-52 |pmc=2890624 |pmid=20487572 |doi-access=free}}</ref> The inaccuracy is based on the assumption that VLDL-C (Very low density lipoprotein cholesterol) is always one-fifth of the triglyceride concentration. Other formulae address this issue by using an adjustable factor<ref>{{cite journal |last1=Martin |first1=Seth S. |last2=Blaha |first2=Michael J. |last3=Elshazly |first3=Mohamed B. |last4=Toth |first4=Peter P. |last5=Kwiterovich |first5=Peter O. |last6=Blumenthal |first6=Roger S. |last7=Jones |first7=Steven R. |title=Comparison of a Novel Method vs. the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile |journal=JAMA |date=20 November 2013 |volume=310 |issue=19 |pages=2061–2068 |doi=10.1001/jama.2013.280532 |pmc=4226221 |pmid=24240933}}</ref> or using a regression equation.<ref>{{cite journal |last1=Sampson |first1=Maureen |last2=Ling |first2=Clarence |last3=Sun |first3=Qian |last4=Harb |first4=Roa |last5=Ashmaig |first5=Mohmed |last6=Warnick |first6=Russell |last7=Sethi |first7=Amar |last8=Fleming |first8=James K. |last9=Otvos |first9=James D. |last10=Meeusen |first10=Jeff W. |last11=Delaney |first11=Sarah R. |last12=Jaffe |first12=Allan S. |last13=Shamburek |first13=Robert |last14=Amar |first14=Marcelo |last15=Remaley |first15=Alan T. |title=A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients With Normolipidemia and/or Hypertriglyceridemia |journal=JAMA Cardiology |date=May 2020 |volume=5 |issue=5 |pages=540–548 |doi=10.1001/jamacardio.2020.0013 |pmc=7240357 |pmid=32101259}}</ref> There are few studies which have compared the LDL-C values derived from this formula and values obtained by direct enzymatic method.<ref name="Ramasamy 1486–1493">{{cite journal |last1=Ramasamy |first1=Jagadish |last2=Job |first2=Victoria |last3=Mani |first3=Thenmozhi |last4=Jacob |first4=Molly |title=Calculated values of serum LDL-cholesterol (LDL-C) – for better or worse? |journal=Nutrition, Metabolism and Cardiovascular Diseases |date=May 2021 |volume=31 |issue=5 |pages=1486–1493 |doi=10.1016/j.numecd.2021.01.016 |pmid=33744036 }}</ref> Direct enzymatic methods are found to be accurate and must be the test of choice in clinical situations. In resource-poor settings, the option to use the formula has to be considered.<ref name="Ramasamy 1486–1493" />

However, the concentration of LDL particles, and to a lesser extent, their size, has a stronger and consistent correlation with individual clinical outcomes than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration) and, to a lesser extent, size have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles.<ref name=snid/> It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number is low, and cardiovascular events are also low.{{cn|date=November 2024}}

====Normal ranges====
In the US, the [[American Heart Association]], [[National Institutes of Health|NIH]], and [[National Cholesterol Education Program|NCEP]] provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of about 2005, these guidelines were:<ref>{{Cite web |title=Cholesterol Levels |url=http://www.americanheart.org/presenter.jhtml?identifier=4500 |access-date=2009-11-14 |publisher=American Heart Association}}</ref><ref>{{Cite web |date=September 2007 |title=What Do My Cholesterol Levels Mean? |url=http://www.americanheart.org/downloadable/heart/119618151049911%20CholLevels%209_07.pdf |access-date=2009-11-14 |publisher=American Heart Association}}</ref><ref>{{Cite web |date=May 2001 |title=Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary |url=http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf |website=National Heart, Lung, and Blood Institute (NHLBI) |publisher=National Institutes of Health}}</ref>

{| class="wikitable"
! Level [[kilogram|mg]]/[[litre|dL]]
! Level [[mole (unit)|mmol]]/L
! Interpretation
|-
| 25 to <50
| <1.3
| Optimal LDL cholesterol levels in healthy young children before onset of atherosclerotic plaque in heart artery walls
|-
| <70
| <1.8
| Optimal LDL cholesterol, corresponding to lower rates of progression, is promoted as a target option for those known to have advanced symptomatic cardiovascular disease clearly
|-
| <100
| <2.6
| Optimal LDL cholesterol, corresponding to lower, but not zero, rates for symptomatic cardiovascular disease events
|-
| 100 to 129
| 2.6 to 3.3
| Near-optimal LDL level, corresponding to higher rates of developing symptomatic cardiovascular disease events
|-
| 130 to 159
| 3.3 to 4.1
| Borderline high LDL level, corresponding to even higher rates for developing symptomatic cardiovascular disease events
|-
| 160 to 199
| 4.1 to 4.9
| High LDL level, corresponding to much higher rates for developing symptomatic cardiovascular disease events
|-
| >200
| >4.9
| Very high LDL level, corresponding to the highest increased rates of symptomatic cardiovascular disease events
|}

Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large [[double blind]], randomized clinical trial of men with [[hypercholesterolemia]];<ref name="pmid7566020 ">{{Cite journal |vauthors=Shepherd J, Cobbe SM, Ford I, et al |date=November 1995 |title=Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group |journal=The New England Journal of Medicine |volume=333 |issue=20 |pages=1301–7 |doi=10.1056/NEJM199511163332001 |pmid=7566020 |doi-access=free}}</ref> far more effective than coronary angioplasty/stenting or bypass surgery.<ref>{{Cite journal |last=William E. Boden |display-authors=etal |date=April 2007 |title=Optimal Medical Therapy with or without PCI for Stable Coronary Disease |journal=The New England Journal of Medicine |volume=356 |issue=15 |pages=1503–1516 |doi=10.1056/NEJMoa070829 |pmid=17387127 |doi-access=free}}</ref>

The 2004 updated American Heart Association, NIH, and NCEP recommendations for people with known atherosclerosis diseases are for lowering LDL levels to less than 70&nbsp;mg/dL. This low level of less than 70&nbsp;mg/dL was recommended for primary prevention of 'very-high risk patients' and secondary prevention as a 'reasonable further reduction'. This position was disputed.<ref>{{Cite journal |last=Hayward |first=Rodney A. |date=3 October 2006 |title=Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem |journal=Ann Intern Med |volume=145 |issue=7 |pages=520–30 |doi=10.7326/0003-4819-145-7-200610030-00010 |pmid=17015870 }}</ref> Statin drugs involved in such clinical trials have [[Pleiotropy (drugs)|numerous physiological effects]] beyond simply the reduction of LDL levels.

From longitudinal population studies following the progression of atherosclerosis-related behaviors from early childhood into adulthood,<ref>{{cite journal |last1=Cybulska |first1=Barbara |last2=Kłosiewicz-Latoszek |first2=Longina |last3=Penson |first3=Peter E. |last4=Nabavi |first4=Seyed Mohammad |last5=Lavie |first5=Carl J. |last6=Banach |first6=Maciej |title=How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors |journal=Progress in Cardiovascular Diseases |date=July 2021 |volume=67 |pages=65–74 |doi=10.1016/j.pcad.2020.12.008 |pmid=33383060 |url=https://researchonline.ljmu.ac.uk/id/eprint/14560/1/How%20low%20should%20you%20go%20with%20LDL%20cholesterol%20lowering%20in%20secondary%20prevention.pdf }}</ref> the usual LDL in childhood, before the development of [[fatty streaks]], is about 35&nbsp;mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not measured low-density lipoprotein concentrations, which is the accurate approach.<ref name="snid">{{Cite journal |vauthors=Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA |date=December 2019 |title=Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review |journal=JAMA Cardiology |volume=4 |issue=12 |pages=1287–1295 |doi=10.1001/jamacardio.2019.3780 |pmc=7369156 |pmid=31642874}}</ref>

A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004,<ref>{{Cite journal |last1=Wolska |first1=Anna |last2=Remaley |first2=Alan T. |year=2020 |title=Measuring LDL-cholesterol: what is the best way to do it? |journal=Current Opinion in Cardiology |volume=35 |issue=4 |pages=405–411 |doi=10.1097/HCO.0000000000000740 |pmc=7360339 |pmid=32412961}}</ref><ref>{{cite journal |last1=Howard |first1=Barbara V. |last2=Robbins |first2=David C. |last3=Sievers |first3=Maurice L. |last4=Lee |first4=Elisa T. |last5=Rhoades |first5=Dorothy |last6=Devereux |first6=Richard B. |last7=Cowan |first7=Linda D. |last8=Gray |first8=R. Stuart |last9=Welty |first9=Thomas K. |last10=Go |first10=Oscar T. |last11=Howard |first11=Wm. James |title=LDL Cholesterol as a Strong Predictor of Coronary Heart Disease in Diabetic Individuals With Insulin Resistance and Low LDL: The Strong Heart Study |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |date=March 2000 |volume=20 |issue=3 |pages=830–835 |doi=10.1161/01.atv.20.3.830 |pmid=10712410}}</ref> neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for diabetes relative to coronary heart disease.<ref name="wang">{{Cite journal |last1=Wang |first1=Y Richard |last2=G Caleb Alexander |last3=David O Meltzer |date=December 2005 |title=Lack of Effect of Guideline Changes on LDL Cholesterol Reporting and Control for Diabetes Visits in the U.S., 1995–2004 |journal=Diabetes Care |volume=28 |issue=12 |pages=2942–2944 |doi=10.2337/diacare.28.12.2942 |pmid=16306559 |doi-access=free}}</ref>

===Direct measurement of LDL particle concentrations===
There are several competing methods for measuring lipoprotein particle concentrations and size. The evidence is that the NMR methodology (developed, automated & significantly reduced in costs while improving accuracy as pioneered by [[Jim Otvos]] and associates) results in a 22-25% reduction in cardiovascular events within one year,<ref>{{Cite journal |last1=Peter P. Toth |last2=Michael Grabner |last3=Rajeshwari S. Punekar |last4=Ralph A. Quimbo |last5=Mark J. Cziraky |last6=Terry A. Jacobson |date=August 2014 |title=Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets |journal=Atherosclerosis |volume=235 |issue=2 |pages=585–591 |doi=10.1016/j.atherosclerosis.2014.05.914 |pmid=24956532 |doi-access=free}}</ref> 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.<ref>{{Cite journal |last=Krauss RM |date=August 2010 |title=Lipoprotein subfractions and cardiovascular disease risk |journal=Current Opinion in Lipidology |volume=21 |issue=4 |pages=305–11 |doi=10.1097/MOL.0b013e32833b7756 |pmid=20531184 }}</ref>

Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $80 US (including shipping) & is decreasing versus the previous costs of >$400 to >$5,000] and higher accuracy. There are two other assays for LDL particles; however, most estimate only LDL particle concentrations like LDL-C.{{cn|date=November 2024}}

The ADA and ACC mentioned direct LDL particle measurement by NMR in a 28 March 2008 joint consensus statement,<ref>{{Cite journal |last1=Brunzell |first1=John D. |last2=Davidson |first2=Michael |last3=Furberg |first3=Curt D. |last4=Goldberg |first4=Ronald B. |last5=Howard |first5=Barbara V. |last6=Stein |first6=James H. |last7=Witztum |first7=Joseph L. |date=15 April 2008 |title=Lipoprotein Management in Patients With Cardiometabolic Risk |journal=J Am Coll Cardiol |volume=51 |issue=15 |pages=1512–1524 |doi=10.1016/j.jacc.2008.02.034 |pmid=18402913}}</ref> as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is less widely available, is more expensive [about $13.00 US (2015 without insurance coverage) from some labs which use the Vantera Analyzer<ref>{{Cite web |title=Google |url=https://www.google.com/#q=Vantera+Analyzer |website=www.google.com}}</ref>]. Debate continues that it is "...unclear whether LDL particle size measurements add value to the measurement of LDL-particle concentration", though outcomes have continuously tracked LDL particle, not LDL-C, concentrations.

Using NMR, the total LDL particle concentrations in nmol/L plasma are typically subdivided by percentiles referenced to the 5,382 men and women participating in the MESA trial who are not on any lipid medications.<ref>{{Cite web |title=MESA - Multi-Ethnic Study of Atherosclerosis |url=https://www.mesa-nhlbi.org/ |website=www.mesa-nhlbi.org}}</ref>

LDL particle concentration can also be measured by measuring the concentration of the protein ApoB, based on the generally accepted principle that each LDL or VLDL particle carries one ApoB molecule.<ref>{{Cite journal |last1=Sniderman |first1=A. D. |last2=Thanassoulis |first2=G. |last3=Glavinovic |first3=T. |last4=Navar |first4=A. M. |last5=Pencina |first5=M. |last6=Catapano |first6=A. |last7=Ference |first7=B. A. |date=1 Dec 2019 |title=Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review |journal=JAMA Cardiology |volume=4 |issue=12 |pages=1287–1295 |doi=10.1001/jamacardio.2019.3780 |pmc=7369156 |pmid=31642874}}</ref>

====Optimal ranges====
The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95%, and >95% groups of the people participating and being tracked in the [[Multi-Ethnic Study of Atherosclerosis|MESA trial]], a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.

{| class="wikitable"
! MESA Percentile
! LDL particles nmol/L
! Interpretation
|-
| 0–20%
| <1,000
| Those with the lowest rate of cardiovascular disease events & low (optimal) LDL particle concentration
|-
| 20–50%
| 1,000–1,299
| Those with a moderate rate of cardiovascular disease events & moderate LDL particle concentration
|-
| 50–80%
| 1,300–1,599
| Those with borderline-high rates of cardiovascular disease events & higher LDL particle concentration
|-
| 89–95%
| 1,600–2,000
| Those with a high rate of cardiovascular disease events and even higher LDL particle concentration
|-
| >95%
| >2,000
| Those with a very high rate of cardiovascular disease events and the highest LDL particle concentration
|-
|}

Over time, the lowest incidence of atherosclerotic events occurs within the <20% group, with increased rates for the higher groups. {{Citation needed |reason="by this table, a generally accepted health LDL concentration of 100 mg/dl would be in the 95th MESA percentile"|date=July 2024}} Multiple other measures, including particle sizes, small LDL particle concentrations, large total and HDL particle concentrations, along with estimations of [[insulin resistance]] pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.

==Lowering LDL-cholesterol==
{| class="wikitable" style="float:right; width:40em; border:solid 1px #999999; margin:0 0 1em 1em;"
|-
! colspan=5 style="background-color: #CCEEEE;" | Markers indicating a need for LDL-C Reduction
(Per 2004 United States Government Minimum Guidelines<ref>{{Cite web |title=Management of Blood Cholesterol in Adults: Systematic Evidence Review from the Cholesterol Expert Panel &#124; National Heart, Lung, and Blood Institute (NHLBI) |url=http://www.nhlbi.nih.gov/health-pro/guidelines/current/cholesterol-guidelines/ |url-status=dead |archive-url=https://web.archive.org/web/20141125175151/http://www.nhlbi.nih.gov/health-pro/guidelines/current/cholesterol-guidelines |archive-date=2014-11-25 |access-date=2014-11-16}}</ref><ref>{{Cite web |title=Archived copy |url=https://www.acli.com/Events/Documents/Tue22812%20-%20Lipidology%20-%20Pamela%20Morris.pdf |url-status=dead |archive-url=https://web.archive.org/web/20160303223001/https://www.acli.com/Events/Documents/Tue22812%20-%20Lipidology%20-%20Pamela%20Morris.pdf |archive-date=2016-03-03 |access-date=2014-11-16}}</ref>)
|-
! If the patient's cardiac risk is...
! then the patient should consider LDL-C reduction if the count in mg/dL is over...
! and LDL-C reduction is indicated if the count in mg/dL is over...
|-
| High, meaning a 20% or greater risk of heart attack within 10 years or an extreme risk factor
| 70<ref name="BBDstatins">{{Citation |author1 = Consumer Reports |author1-link = Consumer Reports |author2 = Drug Effectiveness Review Project |author2-link = Drug Effectiveness Review Project |date = March 2013 |title = Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price |publisher = Consumer Reports |work = Best Buy Drugs |page = 9 |url = http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/StatinsUpdate-FINAL.pdf |access-date = 27 March 2013 }}, which cites
* {{Cite web |last1=United States Department of Health and Human Services |author-link1=United States Department of Health and Human Services |last2=National Heart, Lung, and Blood Institute |author-link2=National Heart, Lung, and Blood Institute |last3=National Institutes of Health |author-link3=National Institutes of Health |date=June 2005 |title=NHLBI, High Blood Cholesterol: What You Need to Know |url=http://www.nhlbi.nih.gov/health/public/heart/chol/wyntk.htm |url-status=dead |archive-url=https://web.archive.org/web/20130401072344/http://www.nhlbi.nih.gov/health/public/heart/chol/wyntk.htm |archive-date=2013-04-01 |access-date=27 March 2013 |website=nhlbi.nih.gov}}</ref>
| 100<ref name="BBDstatins" />
|-
| moderately high, meaning a 10-20% risk of heart attack within 10 years and more than 2 heart attack risk factors
| 100<ref name="BBDstatins" />
| 130<ref name="BBDstatins" />
|-
| moderate, meaning a 10% risk of heart attack within 10 years and more than 2 heart attack risk factors
| 130<ref name="BBDstatins" />
| 160<ref name="BBDstatins" />
|-
| low, meaning less than 10% risk of heart attack within 10 years and 1 or 0 heart attack risk factors
| 160<ref name="BBDstatins" />
| 190<ref name="BBDstatins" />
|-
|}

The [[mevalonate pathway]] serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase ([[HMG CoA reductase]]) is an essential component and performs the first of 37 steps within the cholesterol production pathway, and is present in every animal cell. Statins block this first step.<ref name="Endo1992">{{cite journal | vauthors = Endo A | title = The discovery and development of HMG-CoA reductase inhibitors | journal = Journal of Lipid Research | volume = 33 | issue = 11 | pages = 1569–1582 | date = November 1992 | pmid = 1464741 | doi = 10.1016/S0022-2275(20)41379-3 | doi-access = free | title-link = doi }}</ref>

LDL-C is not a count of actual LDL particles. LDL-C represents how much cholesterol is being transported by all LDL particles, which is either a smaller concentration of large particles or a high concentration of small particles. LDL-C itself can be estimated by subtraction (Friedewald's method)<ref name=h704>{{cite web |title=Laboratory Procedure Manual; Total Cholesterol, HDL-Cholesterol, Triglycerides, and LDL-Cholesterol; Serum; Hitachi 704 |url=https://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l13_c_met_lipids.pdf |website=cdc.gov}}</ref> or directly measured; see the section [[#Testing]] above to see how it's measured.<ref name=pmid34709388>{{cite journal |last1=Sajja |first1=A |last2=Park |first2=J |last3=Sathiyakumar |first3=V |last4=Varghese |first4=B |last5=Pallazola |first5=VA |last6=Marvel |first6=FA |last7=Kulkarni |first7=K |last8=Muthukumar |first8=A |last9=Joshi |first9=PH |last10=Gianos |first10=E |last11=Hirsh |first11=B |last12=Mintz |first12=G |last13=Goldberg |first13=A |last14=Morris |first14=PB |last15=Sharma |first15=G |last16=Blumenthal |first16=RS |last17=Michos |first17=ED |last18=Post |first18=WS |last19=Elshazly |first19=MB |last20=Jones |first20=SR |last21=Martin |first21=SS |title=Comparison of Methods to Estimate Low-Density Lipoprotein Cholesterol in Patients With High Triglyceride Levels. |journal=JAMA Network Open |date=1 October 2021 |volume=4 |issue=10 |pages=e2128817 |doi=10.1001/jamanetworkopen.2021.28817 |pmid=34709388|pmc=8554644 |doi-access=free }}</ref> LDL particles carry many lipid molecules (typically 3,000 to 6,000 lipid molecules per LDL particle); this includes cholesterol, triglycerides, phospholipids and others. An LDL-C measurement cannot account for differences in size and composition between types of LDL.<ref>{{cite journal |last1=McNamara |first1=JR |last2=Small |first2=DM |last3=Li |first3=Z |last4=Schaefer |first4=EJ |title=Differences in LDL subspecies involve alterations in lipid composition and conformational changes in apolipoprotein B. |journal=Journal of Lipid Research |date=September 1996 |volume=37 |issue=9 |pages=1924–35 |doi=10.1016/S0022-2275(20)37557-X |pmid=8895058|doi-access=free }}</ref>

=== Pharmaceutical ===
{{main|Lipid-lowering agent}}
* [[PCSK9 inhibitor]]s, in clinical trials, by several companies, are more effective for LDL reduction than the statins, including statins alone at high dose (though not necessarily the combination of statins plus ezetimibe).{{cn|date=February 2025}} They have been approved and are recommended in patients not receiving enough reduction from their maximally tolerated dose of statins + ezetimibe.<ref name="AlenghatDavis2019">{{cite journal | vauthors = Alenghat FJ, Davis AM | title = Management of Blood Cholesterol | journal = JAMA | volume = 321 | issue = 8 | pages = 800–801 | date = February 2019 | pmid = 30715135 | pmc = 6679800 | doi = 10.1001/jama.2019.0015 }}</ref>
* [[Statin]]s 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 LDL receptors (including hepatic) is increased, resulting in an increased clearance of LDL particles from the extracellular water, including of the blood.<ref name="Endo1992"/>
* [[Ezetimibe]] reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations when combined with statins.<ref>{{Cite web |last=Research |first=Center for Drug Evaluation and |title=Drug Safety Information for Healthcare<!-- "heathcare" in original --> Professionals - Follow-up to the January 25, 2008 Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor) |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079524.htm |website=[[Food and Drug Administration]]}}</ref>
* [[Niacin (substance)|Niacin]] (nicotinic acid), lowers LDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing [[triglyceride]] synthesis and VLDL secretion through a receptor HM74<ref>{{Cite journal |vauthors=Meyers CD, Kamanna VS, Kashyap ML |date=December 2004 |title=Niacin therapy in atherosclerosis |journal=Current Opinion in Lipidology |volume=15 |issue=6 |pages=659–65 |doi=10.1097/00041433-200412000-00006 |pmid=15529025}}</ref> and HM74A or GPR109A.<ref name="pmid17238156">{{Cite journal |vauthors=Soudijn W, van Wijngaarden I, Ijzerman AP |date=May 2007 |title=Nicotinic acid receptor subtypes and their ligands |journal=Medicinal Research Reviews |volume=27 |issue=3 |pages=417–33 |doi=10.1002/med.20102 |pmid=17238156 }}</ref> Introduced in 1955.
* [[Clofibrate]] is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.<ref>{{Cite journal |date=September 1984 |title=WHO cooperative trial on primary prevention of ischemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigators |journal=Lancet |volume=2 |issue=8403 |pages=600–4 |doi=10.1016/s0140-6736(84)90595-6 |pmid=6147641 }}</ref> Other developed and tested [[fibrate]]s, e.g. [[fenofibric acid]]<ref>{{Cite web |title=TRILIPIX (fenofibric acid) |url=https://www.rxabbvie.com/pdf/trilipix_pi.pdf |access-date=7 July 2024}}</ref> have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.
* [[Probucol]], introduced in the 1970s. Now known to work through, among other ways, changing the shape and size of the LDL particle so they can be taken up by the liver without involving the [[LDL receptor]].  It has been discontinued in the west due to HDL-C decreases that were not explainable at the time. It's now known that it enhances the [[reverse cholesterol transport]] and antioxidant functions of HDL despite decreasing HDL-C.<ref name="pmid26125504">{{cite journal |vauthors=Yamashita S, Masuda D, Matsuzawa Y |title=Did we abandon probucol too soon? |journal=Current Opinion in Lipidology |volume=26 |issue=4 |pages=304–16 |date=August 2015 |pmid=26125504 |doi=10.1097/MOL.0000000000000199}}</ref>

====Not approved as drugs ====
* Several [[CETP inhibitor]]s 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.
* Some [[tocotrienol]]s, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production.<ref>{{Cite journal |last1=Song |first1=B.L. |last2=DeBose-Boyd, R.A. |year=2006 |title=Insig-Dependent Ubiquitination and Degradation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Stimulated by Delta- and Gamma-Tocotrienols |journal=J. Biol. Chem. |volume=281 |issue=35 |pages=25054–25601 |doi=10.1074/jbc.M605575200 |pmid=16831864 |doi-access=free}}</ref> As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.{{cn|date=February 2025}}
* [[Phytosterol]]s are widely recognized as having a proven LDL cholesterol lowering efficacy'<ref>{{Cite web |last=European Food Safety Authority, Journal |year=2010 |title=Scientific opinion on the substantiation of health claims related to plant sterols and plant stanols and maintenance of normal blood cholesterol concentrations |url=http://www.efsa.europa.eu/en/efsajournal/pub/1813}}</ref> A 2018 review found a dose-response relationship for phytosterols, with intakes of 1.5 to 3&nbsp;g/day lowering LDL-C by 7.5% to 12%,<ref>{{Cite journal |last1=Trautwein |first1=Elke |last2=Vermeer |first2=Mario |last3=Hiemstra |first3=Harry |last4=Ras |first4=Rouyanne |date=7 September 2018 |title=LDL-Cholesterol Lowering of Plant Sterols and Stanols—Which Factors Influence Their Efficacy? |journal=Nutrients |publisher=MDPI AG |volume=10 |issue=9 |page=1262 |doi=10.3390/nu10091262 |pmc=6163911 |pmid=30205492 |doi-access=free}}</ref> but reviews as of 2017 had found  no data indicating that the consumption of phytosterols may reduce the risk of CVD.<ref>{{Cite journal |last1=Cabral |first1=Carlos Eduardo |last2=Klein |first2=Márcia Regina Simas Torres |year=2017 |title=Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases |journal=Arquivos Brasileiros de Cardiologia |publisher=Sociedade Brasileira de Cardiologia |volume=109 |issue=5 |pages=475–482 |doi=10.5935/abc.20170158 |pmc=5729784 |pmid=29267628}}</ref> Current supplemental guidelines for reducing LDL recommend doses of phytosterols in the 1.6-3.0&nbsp;grams per day range (Health Canada, EFSA, ATP III, FDA) with a 2009 meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15&nbsp;gram per day.<ref>{{Cite journal |last1=Demonty |first1=I. |last2=Ras |first2=R.T. |last3=van der Knaap |first3=H.C. |last4=Duchateau |first4=G.S. |last5=Meijer |first5=L. |last6=Zock |first6=P.L. |last7=Geleijnse |first7=J.M. |last8=Trautwein |first8=E.A. |date=Feb 2009 |title=Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake. |journal=The Journal of Nutrition |volume=139 |issue=2 |pages=271–84 |doi=10.3945/jn.108.095125 |pmid=19091798 |doi-access=free}}</ref>

=== Lifestyle ===
LDL cholesterol can be lowered through dietary intervention by limiting foods with [[saturated fat]] and avoiding foods with [[trans fat]].<ref name=":0">{{Cite web |title=Cholesterol Diet: How Nutrition & Foods Impact Levels |url=https://my.clevelandclinic.org/health/articles/16867-cholesterol--nutrition-tlc |access-date=2024-02-16 |website=Cleveland Clinic |language=en}}</ref> Saturated fats are found in meat products (including poultry), full-fat dairy, eggs, and refined tropical oils like coconut and palm.<ref>{{Cite web |title=Saturated Fat |url=https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/fats/saturated-fats |access-date=2024-02-16 |website=www.heart.org |language=en}}</ref> Added trans fat (in the form of partially hydrogenated oils) has been banned in the US since 2021.<ref>{{Cite journal |last=Nutrition |first=Center for Food Safety and Applied |date=2023-08-30 |title=Trans Fat |url=https://www.fda.gov/food/food-additives-petitions/trans-fat |journal=FDA |language=en}}</ref> However, trans fat can still be found in red meat and dairy products as it is produced in small amounts by ruminants such as sheep and cows.<ref>{{cite book |doi=10.1533/9780857092557.3.383 |quote=In addition to hydrogenated oils, dairy products are a dietary source of trans fatty acids. Ruminant fat contains on average 1–3% trans fatty acids, which originate from the action of ruminant bacteria on feed unsaturated fatty acids.  |chapter=Functional fats and spreads |title=Functional Foods |date=2011 |last1=Turpeinen |first1=A. |last2=Merimaa |first2=P. |pages=383–400 |isbn=978-1-84569-690-0 }}</ref><ref>{{cite book |doi=10.1016/B978-0-12-811297-7.00026-3 |quote=Milk, dairy products, and meat from ruminants contain ∼2%–10% trans fatty acids |chapter=Trans Fatty Acids and Mortality |title=The Molecular Nutrition of Fats |date=2019 |last1=Delgado |first1=Graciela E. |last2=Kleber |first2=Marcus E. |pages=335–345 |isbn=978-0-12-811297-7 }}</ref> LDL cholesterol can also be lowered by increasing consumption of soluble fiber and plant-based foods.<ref>{{cite journal |last1=Schoeneck |first1=Malin |last2=Iggman |first2=David |title=The effects of foods on LDL cholesterol levels: A systematic review of the accumulated evidence from systematic reviews and meta-analyses of randomized controlled trials |journal=Nutrition, Metabolism and Cardiovascular Diseases |date=May 2021 |volume=31 |issue=5 |pages=1325–1338 |doi=10.1016/j.numecd.2020.12.032 |pmid=33762150 }}</ref>

Another lifestyle approach to reduce LDL cholesterol has been minimizing total body fat, in particular fat stored inside the [[abdominal cavity]] ([[Adipose tissue|visceral body fat]]). Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. [[resistin]], which increase [[insulin resistance]] and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of diabetes mellitus.{{cn|date=February 2025}}

== Research ==
Some studies dispute the benefits of low LDL in elderly people, but not in other age groups.<ref>{{cite press release |title=No association between 'bad cholesterol' and elderly deaths |url=https://www.sciencedaily.com/releases/2016/06/160627095006.htm |work=ScienceDaily |publisher=University of South Florida (USF Innovation) |date=27 June 2016 }}</ref>

=== Gene editing ===
In 2021, scientists demonstrated that [[CRISPR gene editing]] can decrease blood levels of LDL cholesterol in ''[[Macaca fascicularis]]'' monkeys for months by 60% via [[Gene knockout|knockout]] of [[PCSK9]] in the [[liver]].<ref>{{Cite news |title=Scientists Gene-Hacked Monkeys to Fix Their Cholesterol |url=https://futurism.com/neoscope/gene-hacked-monkeys-fix-cholesterol |access-date=13 June 2021 |work=Futurism}}</ref><ref>{{cite journal |last1=Musunuru |first1=Kiran |last2=Chadwick |first2=Alexandra C. |last3=Mizoguchi |first3=Taiji |last4=Garcia |first4=Sara P. |last5=DeNizio |first5=Jamie E. |last6=Reiss |first6=Caroline W. |last7=Wang |first7=Kui |last8=Iyer |first8=Sowmya |last9=Dutta |first9=Chaitali |last10=Clendaniel |first10=Victoria |last11=Amaonye |first11=Michael |last12=Beach |first12=Aaron |last13=Berth |first13=Kathleen |last14=Biswas |first14=Souvik |last15=Braun |first15=Maurine C. |last16=Chen |first16=Huei-Mei |last17=Colace |first17=Thomas V. |last18=Ganey |first18=John D. |last19=Gangopadhyay |first19=Soumyashree A. |last20=Garrity |first20=Ryan |last21=Kasiewicz |first21=Lisa N. |last22=Lavoie |first22=Jennifer |last23=Madsen |first23=James A. |last24=Matsumoto |first24=Yuri |last25=Mazzola |first25=Anne Marie |last26=Nasrullah |first26=Yusuf S. |last27=Nneji |first27=Joseph |last28=Ren |first28=Huilan |last29=Sanjeev |first29=Athul |last30=Shay |first30=Madeleine |last31=Stahley |first31=Mary R. |last32=Fan |first32=Steven H. Y. |last33=Tam |first33=Ying K. |last34=Gaudelli |first34=Nicole M. |last35=Ciaramella |first35=Giuseppe |last36=Stolz |first36=Leslie E. |last37=Malyala |first37=Padma |last38=Cheng |first38=Christopher J. |last39=Rajeev |first39=Kallanthottathil G. |last40=Rohde |first40=Ellen |last41=Bellinger |first41=Andrew M. |last42=Kathiresan |first42=Sekar |title=In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates |journal=Nature |date=20 May 2021 |volume=593 |issue=7859 |pages=429–434 |doi=10.1038/s41586-021-03534-y |pmid=34012082 |bibcode=2021Natur.593..429M }}</ref>

==See also==
{{Columns-list|colwidth=30em|
* [[Catechin]]
* [[Cholesterol]]
* [[Lysosomal acid lipase deficiency]]
* [[Cholesteryl ester storage disease]]
* [[Coenzyme Q10]]
* [[Flavonoid]]
* [[Glutathione]]
* [[Health effects of tea]]
* [[High density lipoprotein]]
* [[LDL receptor]]
* [[Lipid profile]]
* [[Lipoprotein(a)]]
* [[Lipoprotein-X]]
* [[Melatonin]]
* [[Polyphenol antioxidant]]
* [[Saturated fat]]
* [[Stanol ester]]
* [[Sterol ester]]
* [[Triglyceride]]
* [[Vitamin A]]
* [[Vitamin C]]
* [[Vitamin E]]
}}

== Notes and references ==
{{Reflist}}

==External links==
* [https://www.youtube.com/watch?v=XPguYN7dcbE Fat (LDL) Degradation]: PMAP [[The Proteolysis Map]]-animation
* [https://web.archive.org/web/20050524010904/http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm Adult Treatment Panel III Full Report]
* [https://web.archive.org/web/20140202053506/http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04.htm ATP III Update 2004]
* {{Cite journal |vauthors=O'Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R |date=June 2004 |title=Optimal low-density lipoprotein is 50 to 70 mg/dL: lower is better and physiologically normal |journal=Journal of the American College of Cardiology |volume=43 |issue=11 |pages=2142–6 |doi=10.1016/j.jacc.2004.03.046 |pmid=15172426}}

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{{DEFAULTSORT:Low-Density Lipoprotein}}
[[Category:Cardiology]]
[[Category:Lipid disorders]]
[[Category:Lipoproteins]]