Editing High-density lipoprotein (section)

== Structure and function ==
With a size ranging from 5 to 17&nbsp;nm, HDL is the smallest of the [[lipoprotein]] particles.<ref name=deng/> It is the densest because it contains the highest proportion of [[protein]] to [[lipids]].<ref name=deng/> Its most abundant [[apolipoprotein]]s are [[Apolipoprotein A1|apo A-I]] and [[Apolipoprotein A2|apo A-II]]. A rare genetic variant, [[ApoA-1 Milano]], has been documented to be far more effective in both protecting against and regressing arterial disease, [[atherosclerosis]].

The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles,<ref name=deng/> whose NMR structure was published;<ref>{{citation |author = Bibow S |display-authors=et al | title = Solution structure of discoidal high-density lipoprotein particles with a shortened apolipoprotein A-I| journal = Nature Structural & Molecular Biology | volume = 24 | issue = 6 | pages = 187–93 | year = 2017 | doi =  10.1038/nsmb.3345|pmid=28024148 |s2cid=27875177 }}</ref> the complexes are capable of picking up cholesterol, carried internally, from cells by interaction with the [[ABCA1|ATP-binding cassette transporter A1 (ABCA1)]].<ref name="pmid24016265">{{cite journal | vauthors = Huang CX, Zhang YL | title = The target of regulating the ATP-binding cassette A1 protein (ABCA1): promoting ABCA1-mediated cholesterol efflux in different cells | journal = Current Pharmaceutical Biotechnology | volume = 14 | issue = 6 | pages = 623–31 | year = 2013 | pmid = 24016265 | doi =  10.2174/138920101131400228}}</ref> A [[Blood plasma|plasma]] enzyme called [[lecithin-cholesterol acyltransferase]] (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually causing the newly synthesized HDL to assume a spherical shape. HDL particles increase in size as they circulate through the blood and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, such as by interaction with the [[ABCG1]] transporter and the [[PLTP|phospholipid transport protein (PLTP)]].<ref name=deng/>

HDL transports cholesterol mostly to the [[liver]] or [[Steroidogenesis|steroidogenic organs]] such as [[adrenal]]s, [[ovary]], and [[testes]] by both direct and indirect pathways. HDL is removed by HDL receptors such as [[SCARB1|scavenger receptor BI]] (SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by [[CETP|cholesteryl ester transfer protein (CETP)]].<ref name=deng/> This protein exchanges triglycerides of [[VLDL]] against cholesteryl esters of HDL. As the result, VLDLs are processed to [[Low-density lipoprotein|LDL]], which are removed from the circulation by the [[LDL receptor]] pathway. The triglycerides are not stable in HDL, but are degraded by [[hepatic lipase]] so that, finally, small HDL particles are left, which restart the uptake of cholesterol from cells.<ref name=deng/>

The cholesterol delivered to the liver is excreted into the [[bile]] and, hence, [[intestine]] either directly or indirectly after conversion into [[bile acid]]s. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of [[steroid hormone]]s.<ref name=deng/>

[[File:hdl1.svg|right|400px]]
Several steps in the metabolism of HDL can participate in the transport of cholesterol from lipid-laden [[macrophages]] of [[atherosclerotic]] [[arteries]], termed [[foam cell]]s, to the liver for secretion into the bile. This pathway has been termed ''[[reverse cholesterol transport]]'' and is considered as the classical protective function of HDL toward atherosclerosis.

HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active. For example, HDL and its protein and lipid constituents help to inhibit [[oxidation]], [[inflammation]], [[Endothelium|activation of the endothelium]], [[coagulation]], and [[Platelet|platelet aggregation]]. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known which are the most important. In addition, a small subfraction of HDL lends protection against the protozoan parasite ''[[Trypanosoma brucei]] brucei''. This HDL subfraction, termed trypanosome lytic factor (TLF), contains specialized proteins that, while very active, are unique to the TLF molecule.<ref name="pmid23059119">{{cite journal | vauthors = Stephens NA, Kieft R, Macleod A, Hajduk SL | title = Trypanosome resistance to human innate immunity: targeting Achilles' heel | journal = Trends in Parasitology | volume = 28 | issue = 12 | pages = 539–45 | date = Dec 2012 | pmid = 23059119 | doi = 10.1016/j.pt.2012.09.002 | pmc = 4687903 }}</ref>

In the [[fight-or-flight response|stress response]], [[serum amyloid A]], which is one of the [[acute-phase proteins]] and an apolipoprotein, is under the stimulation of [[cytokine]]s ([[interleukin 1]], [[interleukin 6]]), and [[cortisol]] produced in the [[adrenal cortex]] and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as [[amyloidosis]].

It has been postulated that the concentration of large HDL particles more accurately reflects protective action, as opposed to the concentration of total HDL particles.<ref>{{cite journal | vauthors = Kwiterovich PO | title = The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: a current review | journal = The American Journal of Cardiology | volume = 86 | issue = 12A | pages = 5L–10L | date = Dec 2000 | pmid = 11374859 | doi = 10.1016/S0002-9149(00)01461-2 }}</ref> This ratio of large HDL to total HDL particles varies widely and is measured only by more sophisticated lipoprotein assays using either [[electrophoresis]] (the original method developed in the 1970s) or newer [[NMR spectroscopy]] methods (See also [[nuclear magnetic resonance]] and [[spectroscopy]]), developed in the 1990s.

=== Subfractions ===
Five subfractions of HDL have been identified.  From largest (and most effective in cholesterol removal) to smallest (and least effective), the types are 2a, 2b, 3a, 3b, and 3c.<ref>{{Cite journal |url=http://circ.ahajournals.org/content/84/1/129 |title=HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. |date=1991 |doi=10.1161/01.CIR.84.1.129 |access-date=2012-06-11 |archive-date=2012-06-18 |archive-url=https://web.archive.org/web/20120618135814/http://circ.ahajournals.org/content/84/1/129 |url-status=live |last1=Salonen |first1=J. T. |last2=Salonen |first2=R. |last3=Seppänen |first3=K. |last4=Rauramaa |first4=R. |last5=Tuomilehto |first5=J. |journal=Circulation |volume=84 |issue=1 |pages=129–139 |pmid=2060089 }}</ref>