Editing Low-density lipoprotein (section)

==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>