Editing Lipoprotein

{{Short description|Biochemical assembly for transporting hydrophobic lipid molecules}}
{{also|Proteolipid|Lipid-anchored protein}}
[[Image:Chylomicron.svg|thumb|250px|Structure of a [[chylomicron]] (the largest lipoprotein).<br />
'''[[Apolipoprotein AI|ApoA]]''', '''[[Apolipoprotein B|ApoB]]''', '''[[Apolipoprotein C|ApoC]]''', '''[[Apolipoprotein E|ApoE]]''' are [[apolipoprotein]]s; green particles are [[phospholipid]]s; '''T''' is [[triglyceride]]; '''C''' is [[cholesterol ester]].]]

A '''lipoprotein''' is a [[biochemical]] assembly whose primary function is to transport [[hydrophobic]] [[lipid]] (also known as [[fat]]) molecules in water, as in [[blood plasma]] or other [[extracellular fluid]]s. They consist of a [[triglyceride]] and [[cholesterol]] center, surrounded by a [[phospholipid]] outer shell, with the [[hydrophilic]] portions oriented outward toward the surrounding water and [[lipophilic]] portions oriented inward toward the lipid center. A special kind of protein, called [[apolipoprotein]], is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.

'''Plasma lipoprotein particles''' are commonly divided into five main classes, based on size, lipid composition, and apolipoprotein content. They are, in increasing size order: [[High-density lipoprotein|HDL]], [[Low-density lipoprotein|LDL]], [[Intermediate-density lipoprotein|IDL]], [[Very-low-density lipoprotein|VLDL]] and [[chylomicron]]s. Subgroups of these plasma particles are primary drivers or modulators of [[atherosclerosis]].<ref>{{cite journal | vauthors = Gofman JW, Jones HB, Lindgren FT, Lyon TP, Elliott HA, Strisower B | title = Blood lipids and human atherosclerosis | journal = Circulation | volume = 2 | issue = 2 | pages = 161–78 | date = August 1950 | pmid = 15427204 | doi = 10.1161/01.CIR.2.2.161 | doi-access = free }}</ref>

Many [[enzyme]]s, [[Membrane transport protein|transporters]], structural proteins, [[antigen]]s, [[Adhesin molecule (immunoglobulin -like)|adhesin]]s, and [[toxin]]s are sometimes also classified as lipoproteins, since they are formed by lipids and proteins.

==Scope==

===Transmembrane lipoproteins===
Some transmembrane [[proteolipid]]s, especially those found in [[bacteria]], are referred to as lipoproteins; they are not related to the lipoprotein particles that this article is about.<ref name=bact>{{cite web |title=Microbial Proteolipids and Lipopeptides - glycopeptidolipids, surfactin, iturnins, polymyxins, daptomycin |url=http://www.lipidhome.co.uk/lipids/simple/lipopep/index.htm |website=The LipidWeb |access-date=21 July 2019}}</ref> Such [[transmembrane protein]]s are difficult to isolate, as they bind tightly to the lipid membrane, often require lipids to display the proper structure, and can be water-insoluble. [[Detergents]] are usually required to isolate transmembrane lipoproteins from their associated biological membranes.

===Plasma lipoprotein particles {{anchor|Plasma lipoproteins particles}}===
{{More citations needed|date=October 2021}}
Because fats are insoluble in water, they cannot be transported on their own in extracellular water, including blood plasma. Instead, they are surrounded by a hydrophilic external shell that functions as a transport vehicle. The role of lipoprotein particles is to transport fat molecules, such as [[triglyceride]]s, phospholipids, and cholesterol within the extracellular water of the body to all the cells and tissues of the body. The proteins included in the external shell of these particles, called apolipoproteins, are synthesized and secreted into the extracellular water by both the [[small intestine]] and [[liver]] cells. The external shell also contains phospholipids and cholesterol.

All [[cell (biology)|cells]] use and rely on fats and cholesterol as building blocks to create the multiple [[cell membrane|membranes]] that cells use both to control internal water content and internal water-soluble elements and to organize their internal structure and protein enzymatic systems. The outer shell of lipoprotein particles have the hydrophilic groups of phospholipids, cholesterol, and apolipoproteins directed outward. Such characteristics make them soluble in the salt-water-based blood pool. [[Triglyceride]]s and [[cholesteryl esters]] are carried internally, shielded from the water by the outer shell. The kind of apolipoproteins contained in the outer shell determines the functional identity of the lipoprotein particles. The interaction of these apolipoproteins with enzymes in the blood, with each other, or with specific proteins on the surfaces of cells, determines whether triglycerides and cholesterol will be added to or removed from the lipoprotein transport particles.

'''Characterization in human plasma'''<ref>{{Cite book|title=Biochemistry|last=Satyanarayana|first=U.|date=2002|publisher=Books and Allied|isbn=8187134801|edition=2nd|location=Kolkata, India|oclc=71209231}}</ref>
{| class="wikitable"
|+
|
!Chylomicrons
!VLDL
!LDL
!HDL
|-
|[[Serum protein electrophoresis|Electrophoretic mobility]]
|Origin
|Pre-Beta
|Beta
|Alpha
|-
|[[Density]]
|less than 0.96
|0.96-1.006
|1.006-1.063
|1.063-1.21
|-
|[[Diameter]] (nm)
|100-1000
|30-90
|20-25
|10-20
|-
|Apolipoproteins
|B<sub>48</sub>, Al, All
|B<sub>100</sub> CI, CII
|B<sub>100</sub>
|AI, AII, CI
|-
|'''Composition'''<br>(% of total content)
|
|
|
|
|-
| · Protein
|2
|10
|20
|40
|-
| · Lipid
|98
|90
|80
|60
|-
|'''Lipid component'''<br>(% of total lipid content)
|
|
|
|
|-
| · Triglycerides
|88
|55
|12
|12
|-
| · Cholesteryl esters
|4
|24
|59
|40
|-
| · Phospholipids
|8
|20
|28
|47
|-
| · Free fatty acids
| -
|1
|1
|1
|}

== Structure ==
Lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesteryl esters and triglycerides. This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins. Plasma lipoproteins, found in [[blood plasma]], are typically divided into five main classes based on size, lipid composition, and apolipoprotein content: [[High-density lipoprotein|HDL]], [[Low-density lipoprotein|LDL]], [[Intermediate-density lipoprotein|IDL]], [[Very-low-density lipoprotein|VLDL]] and [[chylomicron]]s.<ref>{{Citation|last1=Feingold|first1=Kenneth R.|title=Introduction to Lipids and Lipoproteins|date=2000|url=http://www.ncbi.nlm.nih.gov/books/NBK305896/|work=Endotext|editor-last=Feingold|editor-first=Kenneth R.|place=South Dartmouth (MA)|publisher=MDText.com, Inc.|pmid=26247089|access-date=2020-12-10|last2=Grunfeld|first2=Carl|editor2-last=Anawalt|editor2-first=Bradley|editor3-last=Boyce|editor3-first=Alison|editor4-last=Chrousos|editor4-first=George}}</ref>

== Functions ==

=== Metabolism ===
The handling of lipoprotein particles in the body is referred to as ''lipoprotein particle metabolism''. It is divided into two pathways, [[exogenous]] and [[endogenous]], depending in large part on whether the lipoprotein particles in question are composed chiefly of dietary (exogenous) lipids or whether they originated in the liver (endogenous), through [[de novo synthesis]] of triglycerides.

The [[hepatocyte]]s are the main platform for the handling of triglycerides and cholesterol; the liver can also store certain amounts of [[glycogen]] and triglycerides. While [[adipocyte]]s are the main storage cells for triglycerides, they do not produce any lipoproteins.

====Exogenous pathway====
[[File:Lipoprotein metabolism.png|500px|thumbnail|right|Simplified flowchart showing the essentials of lipoprotein metabolism.]]

[[Bile]] emulsifies fats contained in the [[chyme]], then [[pancreatic lipase]] cleaves triglyceride molecules into two fatty acids and one 2-monoacylglycerol. [[Enterocyte]]s readily absorb the small molecules from the chymus. Inside of the enterocytes, fatty acids and [[monoacylglyceride]]s are transformed again into triglycerides. Then these lipids are assembled with [[apolipoprotein B-48]] into ''nascent [[chylomicron]]s''. These particles are then secreted into the [[lacteal]]s in a process that depends heavily on apolipoprotein B-48. As they circulate through the [[lymphatic vessels]], nascent chylomicrons bypass the liver circulation and are drained via the [[thoracic duct]] into the bloodstream.

In the blood stream, ''nascent chylomicron particles'' interact with HDL particles, resulting in HDL donation of [[apolipoprotein C-II]] and [[apolipoprotein E]] to the nascent chylomicron. The chylomicron at this stage is then considered mature. Via apolipoprotein C-II, mature chylomicrons activate [[lipoprotein lipase]] (LPL), an enzyme on [[endothelial cell]]s lining the blood vessels. LPL catalyzes the [[hydrolysis]] of triglycerides that ultimately releases glycerol and [[fatty acid]]s from the chylomicrons. Glycerol and fatty acids can then be absorbed in peripheral tissues, especially [[Adipose tissue|adipose]] and [[Muscle tissue|muscle]], for energy and storage.

The hydrolyzed chylomicrons are now called ''chylomicron remnants''. The chylomicron remnants continue circulating the bloodstream until they interact via apolipoprotein E with chylomicron remnant receptors, found chiefly in the liver. This interaction causes the [[endocytosis]] of the chylomicron remnants, which are subsequently hydrolyzed within [[lysosome]]s. Lysosomal [[hydrolysis]] releases glycerol and fatty acids into the cell, which can be used for energy or stored for later use.

====Endogenous pathway====
The liver is the central platform for the handling of lipids: it is able to store glycerols and fats in its cells, the [[hepatocytes]]. Hepatocytes are also able to create triglycerides via de novo synthesis. They also produce the bile from cholesterol. The intestines are responsible for absorbing cholesterol. They transfer it over into the blood stream.

In the hepatocytes, triglycerides and cholesteryl esters are assembled with [[apolipoprotein B-100]] to form ''nascent VLDL particles''. Nascent VLDL particles are released into the bloodstream via a process that depends upon apolipoprotein B-100.

In the blood stream, ''nascent VLDL particles'' bump with HDL particles; as a result, HDL particles donate [[apolipoprotein C-II]] and apolipoprotein E to the nascent VLDL particle. Once loaded with apolipoproteins C-II and E, the nascent VLDL particle is considered mature. VLDL particles circulate and encounter LPL expressed on [[endothelial cell]]s. Apolipoprotein C-II activates LPL, causing hydrolysis of the VLDL particle and the release of glycerol and fatty acids. These products can be absorbed from the blood by peripheral tissues, principally adipose and muscle. The hydrolyzed VLDL particles are now called [[Remnant cholesterol|VLDL remnants]] or [[intermediate-density lipoprotein]]s (IDLs). VLDL remnants can circulate and, via an interaction between apolipoprotein E and the remnant receptor, be absorbed by the liver, or they can be further hydrolyzed by [[hepatic lipase]].

Hydrolysis by hepatic lipase releases glycerol and fatty acids, leaving behind ''IDL remnants'', called [[low-density lipoprotein]]s (LDL), which contain a relatively high cholesterol content<ref name="pmid21573056">{{cite journal | vauthors = Kumar V, Butcher SJ, Öörni K, Engelhardt P, Heikkonen J, Kaski K, Ala-Korpela M, Kovanen PT | 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 | date = May 2011 | pmid = 21573056 | pmc = 3090388 | doi = 10.1371/journal.pone.0018841 | bibcode = 2011PLoSO...618841K | doi-access = free }}</ref> ({{YouTube|id=CtFwss81GBk|title=see native LDL structure at 37°C}}). LDL circulates and is absorbed by the liver and peripheral cells. Binding of LDL to its target tissue occurs through an interaction between the [[LDL receptor]] and apolipoprotein B-100 on the LDL particle. Absorption occurs through [[endocytosis]], and the internalized LDL particles are hydrolyzed within lysosomes, releasing lipids, chiefly cholesterol.

=== Possible role in oxygen transport ===
Plasma lipoproteins may carry oxygen gas.<ref>{{Cite journal|last1=Petyaev|first1=I. M.|last2=Vuylsteke|first2=A.|last3=Bethune|first3=D. W.|last4=Hunt|first4=J. V.|date=1998|title=Plasma oxygen during cardiopulmonary bypass: a comparison of blood oxygen levels with oxygen present in plasma lipid|journal=Clinical Science |volume=94|issue=1|pages=35–41|doi=10.1042/cs0940035|issn=0143-5221|pmid=9505864}}</ref> This property is due to the crystalline hydrophobic structure of lipids, providing a suitable environment for O<sub>2</sub> solubility compared to an aqueous medium.<ref>{{Cite journal|last1=Bacić|first1=G.|last2=Walczak|first2=T.|last3=Demsar|first3=F.|last4=Swartz|first4=H. M.|date=October 1988|title=Electron spin resonance imaging of tissues with lipid-rich areas|journal=Magnetic Resonance in Medicine|volume=8|issue=2|pages=209–219|doi=10.1002/mrm.1910080211|issn=0740-3194|pmid=2850439|s2cid=41810978}}</ref>

=== Role in inflammation ===
[[Inflammation]], a biological system response to stimuli such as the introduction of a [[pathogen]], has an underlying role in numerous systemic biological functions and pathologies. This is a useful response by the immune system when the body is exposed to pathogens, such as bacteria in locations that will prove harmful, but can also have detrimental effects if left unregulated. It has been demonstrated that lipoproteins, specifically HDL, have important roles in the inflammatory process.<ref name=":0">{{cite journal | vauthors = Namiri-Kalantari R, Gao F, Chattopadhyay A, Wheeler AA, Navab KD, Farias-Eisner R, Reddy ST | title = The dual nature of HDL: Anti-Inflammatory and pro-Inflammatory | journal = BioFactors | volume = 41 | issue = 3 | pages = 153–9 | date = May 2015 | pmid = 26072738 | doi = 10.1002/biof.1205 | s2cid = 28785539 }}</ref>

When the body is functioning under normal, stable physiological conditions, HDL has been shown to be beneficial in several ways.<ref name=":0" /> LDL contains apolipoprotein B (apoB), which allows LDL to bind to different tissues, such as the artery wall if the [[glycocalyx]] has been damaged by high [[blood sugar level]]s.<ref name=":0" /> If oxidised, the LDL can become trapped in the proteoglycans, preventing its removal by HDL cholesterol efflux.<ref name=":0" /> Normal functioning HDL is able to prevent the process of oxidation of LDL and the subsequent inflammatory processes seen after oxidation.<ref name=":0" />

[[Lipopolysaccharide]], or LPS, is the major pathogenic factor on the cell wall of [[Gram-negative bacteria]]. [[Gram-positive bacteria]] has a similar component named [[Lipoteichoic acid]], or LTA. HDL has the ability to bind LPS and LTA, creating HDL-LPS complexes to neutralize the harmful effects in the body and clear the LPS from the body.<ref name=":1">{{cite book | vauthors = Pirillo A, Catapano AL, Norata GD | title = High Density Lipoproteins | chapter = HDL in infectious diseases and sepsis | series = Handbook of Experimental Pharmacology | volume = 224 | pages = 483–508 | date = 2015 | publisher = Springer | pmid = 25522999 | doi = 10.1007/978-3-319-09665-0_15 | hdl = 2434/274561 | isbn = 978-3-319-09664-3 }}</ref> HDL also has significant roles interacting with cells of the immune system to modulate the availability of cholesterol and modulate the immune response.<ref name=":1" />

Under certain abnormal physiological conditions such as system [[infection]] or [[sepsis]], the major components of HDL become altered,<ref name=":1" /><ref name=":2">{{cite journal | vauthors = Norata GD, Pirillo A, Ammirati E, Catapano AL | title = Emerging role of high density lipoproteins as a player in the immune system | journal = Atherosclerosis | volume = 220 | issue = 1 | pages = 11–21 | date = January 2012 | pmid = 21783193 | doi = 10.1016/j.atherosclerosis.2011.06.045 }}</ref> The composition and quantity of lipids and apolipoproteins are altered as compared to normal physiological conditions, such as a decrease in HDL cholesterol (HDL-C), phospholipids, apoA-I (a major lipoprotein in HDL that has been shown to have beneficial anti-inflammatory properties), and an increase in [[Serum amyloid A]].<ref name=":1" /><ref name=":2" /> This altered composition of HDL is commonly referred to as acute-phase HDL in an acute-phase inflammatory response, during which time HDL can lose its ability to inhibit the oxidation of LDL.<ref name=":0" /> In fact, this altered composition of HDL is associated with increased mortality and worse clinical outcomes in patients with sepsis.<ref name=":1" />

==Classification==

===By density===
Lipoproteins may be classified as five major groups, listed from larger and lower density to smaller and higher density. Lipoproteins are larger and less dense when the fat to protein ratio is increased. They are classified on the basis of [[electrophoresis]], [[ultracentrifugation]] and [[nuclear magnetic resonance spectroscopy]] via the [https://www.youtube.com/watch?v=OkKn4pLY3AU   Vantera Analyzer].<ref>{{cite web|title=Vantera Clinical Analyzer - MDEA 2013 Finalist|url=https://www.youtube.com/watch?v=OkKn4pLY3AU|website=YouTube.com|publisher=LipoScience, Inc. <!--|archive-url=https://www.google.com/#q=LipoScience+Inc.-->|location=2500 Sumner Blvd, Raleigh, NC 27616}}</ref>
* [[Chylomicron]]s carry triglycerides (fat) from the intestines to the liver, to [[skeletal muscle]], and to adipose tissue.
* [[Very-low-density lipoprotein]]s (VLDL) carry (newly synthesised) triglycerides from the liver to adipose tissue.
* [[Intermediate-density lipoprotein]]s (IDL) are intermediate between VLDL and LDL. They are not usually detectable in the blood when [[fasting]].
* [[Low-density lipoprotein]]s (LDL) carry 3,000 to 6,000 fat molecules (phospholipids, cholesterol, triglycerides, etc.) around the body. LDL particles are sometimes referred to as "bad" lipoprotein because concentrations of two kinds of LDL (sd-LDL and LPA), correlate with atherosclerosis progression. In healthy individuals, most LDL is large and buoyant (lb LDL).
** large buoyant LDL (lb LDL) particles
** small dense LDL (sd LDL) particles
** [[Lipoprotein(a)]] (LPA) is a lipoprotein particle of a certain phenotype
* [[High-density lipoprotein]]s (HDL) collect fat molecules from the body's cells/tissues and take them back to the liver. HDLs are sometimes referred to as "good" lipoprotein because higher concentrations correlate with low rates of atherosclerosis progression and/or regression.

For young healthy research subjects, ~70&nbsp;kg (154&nbsp;lb), these data represent averages across individuals studied, percentages represent % dry weight:
{| cellpadding=3 cellspacing=0 border=1 style="border-collapse:collapse"
|bgcolor="#cccccc"| '''Density''' (g/m[[Litre|L]])
|bgcolor="#cccccc"| '''Class'''
|bgcolor="#cccccc"| '''Diameter''' (nm)
|bgcolor="#cccccc"| '''% protein'''
|bgcolor="#cccccc"| '''% cholesterol & cholesterol ester'''
|bgcolor="#cccccc"| '''% phospholipid'''
|bgcolor="#cccccc"| '''% triglyceride<br />'''
|-
| >1.063
| [[High-density lipoprotein|HDL]]
| 5–15
| 33
| 30
| 29
| 4-8
|-
| 1.019–1.063
| [[Low-density lipoprotein|LDL]]
| 18–28
| 25
| 46-50
| 21-22
| 8-10
|-
| 1.006–1.019
| [[Intermediate-density lipoprotein|IDL]]
| 25–50
| 18
| 29
| 22
| 31
|-
| 0.95–1.006
| [[VLDL]]
| 30–80
| 10
| 22
| 18
| 50
|-
| <0.95
| [[Chylomicrons]]
| 75-1200
| 1-2
| 8
| 7
| 83-84
|} <ref>''Biochemistry'' 2nd Ed. 1995 Garrett & Grisham</ref><ref>''Principles of Biochemistry'' 2nd Ed. 1995 Zubay, Parson and Vance</ref> However, these data are not necessarily reliable for any one individual or for the general clinical population.

===Alpha and beta===
It is also possible to classify lipoproteins as "alpha" and "beta", according to the classification of proteins in [[serum protein electrophoresis]]. This terminology is sometimes used in describing lipid disorders such as [[abetalipoproteinemia]].

===Subdivisions===
Lipoproteins, such as LDL and HDL, can be further subdivided into subspecies isolated through a variety of methods.<ref name=":3">{{cite journal | vauthors = Shah AS, Tan L, Long JL, Davidson WS | title = Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond | journal = Journal of Lipid Research | volume = 54 | issue = 10 | pages = 2575–85 | date = October 2013 | pmid = 23434634 | pmc = 3770071 | doi = 10.1194/jlr.R035725  |doi-access=free }}</ref><ref>{{cite journal | vauthors = Garcia-Rios A, Nikolic D, Perez-Martinez P, Lopez-Miranda J, Rizzo M, Hoogeveen RC | title = LDL and HDL subfractions, dysfunctional HDL: treatment options | journal = Current Pharmaceutical Design | volume = 20 | issue = 40 | pages = 6249–55 | date = 2014 | pmid = 24953394 | doi = 10.2174/1381612820666140620154014 }}</ref> These are subdivided by density or by the protein contents/ proteins they carry.<ref name=":3" /> While the research is currently ongoing, researchers are learning that different subspecies contain different apolipoproteins, proteins, and lipid contents between species which have different physiological roles.<ref name=":3" /> For example, within the HDL lipoprotein subspecies, a large number of proteins are involved in general lipid metabolism.<ref name=":3" /> However, it is being elucidated that HDL subspecies also contain proteins involved in the following functions: [[homeostasis]], [[fibrinogen]], [[Coagulation|clotting cascade]], inflammatory and immune responses, including the [[complement system]], [[proteolysis]] inhibitors, [[Acute-phase protein|acute-phase response]] proteins, and the [[Lipopolysaccharide binding protein|LPS-binding protein]], [[heme]] and iron metabolism, [[platelet]] regulation, vitamin binding and general transport.<ref name=":3" />

==Research ==
High levels of lipoprotein(a) are a significant [[Risk factor (epidemiology)|risk factor]] for [[Atherosclerosis|atherosclerotic]] [[cardiovascular disease]]s via mechanisms associated with [[inflammation]] and [[thrombosis]].<ref name="aha">{{cite journal |vauthors=Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, Lloyd-Jones DM, Marcovina SM, Yeang C, Koschinsky ML |title=Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=42 |issue=1 |pages=e48–e60 |date=January 2022 |pmid=34647487 |pmc=9989949 |doi=10.1161/ATV.0000000000000147}}</ref> The links of mechanisms between different lipoprotein isoforms and risk for cardiovascular diseases, lipoprotein synthesis, regulation, and metabolism, and related risks for [[genetic disease]]s are under active research, as of 2022.<ref name=aha/>

== See also ==
* [[Lipid anchored protein]]
* [[Remnant cholesterol]]
* [[Reverse cholesterol transport]]
* [[Vertical Auto Profile]]

== References ==
{{Reflist}}

== External links ==
* {{MeshName|Lipoproteins}}

{{Membrane lipids}}
{{Lipoproteins}}

{{Authority control}}

[[Category:Lipids]]
[[Category:Lipoproteins|*]]
[[Category:Physiology]]
[[Category:Cardiology]]

[[he:כולסטרול#ליפופרוטאינים]]