Editing High-density lipoprotein

{{short description|One of the five major groups of lipoprotein}}
''' High-density lipoprotein '''('''HDL''') is one of the five major groups of [[lipoprotein]]s.<ref>{{cite web|title=LDL and HDL: Bad and Good Cholesterol|url=https://www.cdc.gov/cholesterol/ldl_hdl.htm|website=Centers for Disease Control and Prevention|publisher=CDC|access-date=11 September 2017|ref=cdc-hdl-ldl|archive-date=12 September 2017|archive-url=https://web.archive.org/web/20170912102144/https://www.cdc.gov/cholesterol/ldl_hdl.htm|url-status=live}}</ref> Lipoproteins are complex particles composed of multiple proteins which transport all [[fat]] molecules ([[lipid]]s) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle (organized by one, two or three [[Apolipoprotein A1|ApoA]]). HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.<ref name="deng">{{cite book |vauthors=Deng S, Xu Y, Zheng L |title=HDL Metabolism and Diseases |chapter=HDL Structure |series=Advances in Experimental Medicine and Biology |volume=1377 |pages=1–11 |date=2022 |pmid=35575917 |doi=10.1007/978-981-19-1592-5_1 |isbn=978-981-19-1591-8 |chapter-url=}}</ref>

HDL particles are commonly referred to as "good cholesterol", because they transport fat molecules out of artery walls, reduce [[macrophage]] accumulation, and thus help prevent or even regress [[atherosclerosis]].<ref name=am180/> 

==Overview==
Lipoproteins are divided into five subgroups, by density/size (an inverse relationship), which also correlates with function and incidence of cardiovascular events. Unlike the larger lipoprotein particles, which deliver fat molecules to cells, HDL particles remove fat molecules from cells. The lipids carried include [[cholesterol]], [[phospholipids]], and [[triglycerides]], amounts of each are variable.<ref>{{cite book |vauthors=Kontush A, Lindahl M, Lhomme M, Calabresi L, Chapman MJ, Davidson WS |title=High Density Lipoproteins |chapter=Structure of HDL: particle subclasses and molecular components |series=Handbook of Experimental Pharmacology |volume=224 |issue= <!-- --> |pages=3–51 |date=2015 |pmid=25522985 |doi=10.1007/978-3-319-09665-0_1 |isbn=978-3-319-09664-3 |doi-access=free }}</ref>

HDL particles remove fats and cholesterol from cells, including within [[artery]] wall [[atheroma]], and transport it back to the liver for excretion or re-use. Increasing concentrations of HDL particles in the blood are associated with decreasing accumulation of [[atherosclerosis]] within the walls of arteries,<ref>{{cite journal |vauthors=Casula M, Colpani O, Xie S, Catapano AL, Baragetti A |title=HDL in Atherosclerotic Cardiovascular Disease: In Search of a Role |journal=Cells |volume=10 |issue=8 |date=July 2021 |page=1869 |pmid=34440638 |pmc=8394469 |doi=10.3390/cells10081869 |url=|doi-access=free }}</ref> reducing the risk of [[Vulnerable plaque|sudden plaque ruptures]], [[cardiovascular disease]], [[stroke]] and other [[vascular disease]]s.<ref name=deng/> People with higher levels of HDL-C tend to have fewer problems with [[cardiovascular diseases]], while those with low HDL-C cholesterol levels (especially less than 40&nbsp;mg/dL or about 1&nbsp;mmol/L) have increased rates for heart disease.<ref>{{cite journal | vauthors = Toth PP | title = Cardiology patient page. The "good cholesterol": high-density lipoprotein | journal = Circulation | volume = 111 | issue = 5 | pages = e89–e91 | date = Feb 2005 | pmid = 15699268 | doi = 10.1161/01.CIR.0000154555.07002.CA | doi-access = free }}</ref>{{update inline|date=July 2022}} Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people.<ref>{{cite web | url= http://eurheartjsupp.oxfordjournals.org/content/8/suppl_F/F4.full | archive-url= https://web.archive.org/web/20150201022804/http://eurheartjsupp.oxfordjournals.org/content/8/suppl_F/F4.full | url-status= dead | archive-date= 2015-02-01 | last=Sirtori | first=Cesare R. | title=HDL and the progression of atherosclerosis: new insights | date=October 2006 | work=European Heart Journal Supplements}}</ref>{{update inline|date=July 2022}}

However, a higher blood level of HDL is not necessarily protective against cardiovascular disease and may even be harmful in extremely high quantities,<ref name="pmid34572269">{{cite journal | vauthors = Franczyk B, Rysz J, Ławiński J, Rysz-Górzyńska M, Gluba-Brzózka A | title = Is a High HDL-Cholesterol Level Always Beneficial? | journal = Biomedicines | volume = 9 | issue = 9 | date = August 2021 | page = 1083 | pmid = 34572269 | pmc = 8466913 | doi = 10.3390/biomedicines9091083 | doi-access = free }}</ref> with an increased cardiovascular risk, especially in hypertensive patients.<ref>{{cite journal |vauthors=Trimarco V, Izzo R, Morisco C, Mone P, Maria Virginia M, Falco A, Pacella D, Gallo P, Lembo M, Santulli G, Trimarco B |title=High HDL (High-Density Lipoprotein) Cholesterol Increases Cardiovascular Risk in Hypertensive Patients |journal=Hypertension |volume= 79|issue= 10|pages=2355–2363 |date=August 2022 |pmid=35968698 |doi=10.1161/HYPERTENSIONAHA.122.19912 |pmc=9617028 |url=}}</ref>

== Testing ==
Because of the high cost of directly measuring HDL particles, [[blood tests]] commonly measure a surrogate value, HDL-cholesterol (HDL-C), i.e. the cholesterol associated with HDL particles. 
HDL-C is often contrasted with the amount of cholesterol estimated to be carried within [[Low-density lipoprotein|low-density lipoprotein particles]], known as LDL-C, with HDL-C being nicknamed "good cholesterol" and LDL-C "bad cholesterol". 

In healthy individuals, about 30% of blood cholesterol, along with other fats, is carried by HDL.<ref name="am180">{{cite web |url=https://www.heart.org/en/health-topics/cholesterol/hdl-good-ldl-bad-cholesterol-and-triglycerides |title=HDL (Good), LDL (Bad) Cholesterol and Triglycerides |publisher=[[American Heart Association]] |date=2021 |access-date=31 May 2021 |archive-date=28 July 2018 |archive-url=https://web.archive.org/web/20180728080038/http://www.heart.org/HEARTORG/Conditions/Cholesterol/HDLLDLTriglycerides/HDL-Good-LDL-Bad-Cholesterol-and-Triglycerides_UCM_305561_Article.jsp |url-status=live }}</ref> This is often contrasted with the amount of cholesterol estimated to be carried within low-density lipoprotein particles, [[Low-density lipoprotein|LDL]], and called LDL-C. HDL particles remove fats and cholesterol from cells, including within [[artery]] wall [[atheroma]], and transport it back to the liver for excretion or re-utilization; thus the cholesterol carried within HDL particles (HDL-C) is sometimes called "good cholesterol". Those with higher levels of HDL-C tend to have fewer problems with [[cardiovascular diseases]], while those with low HDL-C cholesterol levels (especially less than 40&nbsp;mg/dL or about 1&nbsp;mmol/L) have increased rates for heart disease.<ref>{{cite journal | vauthors = Toth PP | title = Cardiology patient page. The "good cholesterol": high-density lipoprotein | journal = Circulation | volume = 111 | issue = 5 | pages = e89–e91 | date = Feb 2005 | pmid = 15699268 | doi = 10.1161/01.CIR.0000154555.07002.CA | doi-access = free }}</ref>{{update inline
|date=July 2022}} Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people.<ref>{{cite web | url= http://eurheartjsupp.oxfordjournals.org/content/8/suppl_F/F4.full | archive-url= https://web.archive.org/web/20150201022804/http://eurheartjsupp.oxfordjournals.org/content/8/suppl_F/F4.full | url-status= dead | archive-date= 2015-02-01 | last=Sirtori | first=Cesare R. | title=HDL and the progression of atherosclerosis: new insights | date=October 2006 | work=European Heart Journal Supplements}}</ref>{{update inline|date=July 2022}}

The remainder of the serum cholesterol after subtracting the HDL is the '''non-HDL cholesterol'''. The concentration of these other components, which may cause [[atheroma]], is known as the '''non-HDL-C'''. This is now preferred to LDL-C as a secondary marker as it has been shown to be a better predictor and it is more easily calculated.<ref>{{citation |author=M.J. Sorrentino |pages=86–87 |title=Hyperlipidemia in Primary Care |chapter=Non-HDL-Cholesterol |year=2011 |publisher=Springer |isbn=978-1-60327-502-6}}</ref>

== 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>

== Epidemiology ==
Men tend to have noticeably lower HDL concentrations, with smaller size and lower cholesterol content, than women. Men also have a greater incidence of [[atherosclerosis|atherosclerotic]] heart disease. Studies confirm the fact that HDL has a buffering role in balancing the effects of the hypercoagulable state in type 2 diabetics and decreases the high risk of cardiovascular complications in these patients. Also, the results obtained in this study revealed that there was a significant negative correlation between HDL and [[Partial thromboplastin time|activated partial thromboplastin time]] (APTT).{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

Epidemiological studies have shown that high concentrations of HDL (over 60&nbsp;mg/dL) have protective value against [[cardiovascular disease]]s such as ischemic stroke and [[myocardial infarction]]. Low concentrations of HDL (below 40&nbsp;mg/dL for men, below 50&nbsp;mg/dL for women) increase the risk for [[atherosclerotic]] diseases.<ref>{{Cite journal |last1=Ahmed |first1=Haitham M. |last2=Miller |first2=Michael |last3=Nasir |first3=Khurram |last4=McEvoy |first4=John W. |last5=Herrington |first5=David |last6=Blumenthal |first6=Roger S. |last7=Blaha |first7=Michael J. |date=2016-05-15 |title=Primary Low Level of High-Density Lipoprotein Cholesterol and Risks of Coronary Heart Disease, Cardiovascular Disease, and Death: Results From the Multi-Ethnic Study of Atherosclerosis |journal=American Journal of Epidemiology |volume=183 |issue=10 |pages=875–883 |doi=10.1093/aje/kwv305 |issn=0002-9262 |pmc=4867155 |pmid=27189327}}</ref>

Data from the landmark [[Framingham Heart Study]] showed that, for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. On the converse, however, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.<ref>{{cite journal | vauthors = Rahilly-Tierney CR, Spiro A, Vokonas P, Gaziano JM | title = Relation between high-density lipoprotein cholesterol and survival to age 85 years in men (from the VA normative aging study) | journal = The American Journal of Cardiology | volume = 107 | issue = 8 | pages = 1173–7 | date = Apr 2011 | pmid = 21296318 | doi = 10.1016/j.amjcard.2010.12.015 }}</ref><ref>{{cite journal | vauthors = Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ, Faas FH, Anderson JW | title = Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT) | journal = Archives of Internal Medicine | volume = 162 | issue = 22 | pages = 2597–604 | year = 2002 | pmid = 12456232 | doi = 10.1001/archinte.162.22.2597 | doi-access = free }}</ref>  <!--The prior sentences make more sense than this garbled explanation of it...So, for example, for a fixed LDL level of 220 mg/dl, the risk of coronary heart disease is 3-times normal if the HDL is low (25 mg/dl) but just one-third of normal if the HDL is high (85 mg/dl). On the other hand, for a fixed HDL level of 85 mg/dl, the risk of coronary heart disease is one-tenth normal if the LDL is low (100 mg/dl) and still only three-tenths of normal if the LDL is high (220 mg/dl). Phrased differently, this data implies that HDL is a more potent risk factor than LDL. Indeed, for a high HDL level (85 mg/dl), the risk of coronary disease remains lower than average even when the LDL level is high. Lowering LDL levels in such people, while of some benefit, merely converts a low risk situation to a very low risk situation.-->

Even people with very low LDL levels achieved by [[statin]] treatment are exposed to increased risk if their HDL levels are not high enough.<ref>{{cite journal | vauthors = Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC | title = HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events | journal = The New England Journal of Medicine | volume = 357 | issue = 13 | pages = 1301–10 | date = Sep 2007 | pmid = 17898099 | doi = 10.1056/NEJMoa064278 | author10 = Treating to New Targets Investigators | s2cid = 44794291 | doi-access = free }}</ref>{{Non-primary source needed|date=April 2024}}

Very high HDL-C levels (≥80&nbsp;mg/dL in men, ≥100&nbsp;mg/dL in women) appears to be detrimental to cardiovascular outcomes. Several genetic conditions cause abnormally low or high HDL-C levels, often without the expected change in cardiovascular disease rates.  In fact, when many known correlates of CVD risks are controlled for, HDL-C does not have any correlation with cardiovascular event risks. In this way, HDL-C only seems to serve as an imperfect, but easy-to-measure, proxy for a healthy lifestyle. What does correlate well with CVD risks even when these factors are controlled for is a direct measure of the capability for [[reverse cholesterol transport]] in a person's blood serum, the ''cholesterol efflux capacity'' (CEC).<ref name=Razavi>{{cite journal |last1=Razavi |first1=AC |last2=Jain |first2=V |last3=Grandhi |first3=GR |last4=Patel |first4=P |last5=Karagiannis |first5=A |last6=Patel |first6=N |last7=Dhindsa |first7=DS |last8=Liu |first8=C |last9=Desai |first9=SR |last10=Almuwaqqat |first10=Z |last11=Sun |first11=YV |last12=Vaccarino |first12=V |last13=Quyyumi |first13=AA |last14=Sperling |first14=LS |last15=Mehta |first15=A |title=Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease? |journal=The Journal of Clinical Endocrinology and Metabolism |date=18 January 2024 |volume=109 |issue=2 |pages=321–332 |doi=10.1210/clinem/dgad406 |pmid=37437107|pmc=11032254 }}</ref>

== Estimating HDL via associated cholesterol ==
Clinical laboratories formerly measured HDL cholesterol by separating other lipoprotein fractions using either ultracentrifugation or chemical precipitation with divalent ions such as Mg<sup>2+</sup>, then coupling the products of a cholesterol oxidase reaction to an indicator reaction. The reference method still uses a combination of these techniques.<ref>{{cite web|title=National Reference System for Cholesterol – Cholesterol Reference Method Laboratory Network – HDL Cholesterol Certification Protocol for Manufacturers|url=https://www.cdc.gov/labstandards/pdf/crmln/MFRHDLNov2002final.pdf|publisher=CDC|access-date=10 November 2013|archive-date=10 November 2013|archive-url=https://web.archive.org/web/20131110213548/http://www.cdc.gov/labstandards/pdf/crmln/MFRHDLNov2002final.pdf|url-status=live}}</ref> Most laboratories now use automated homogeneous analytical methods in which lipoproteins containing [[Apolipoprotein B|apo B]] are blocked using antibodies to apo B, then a [[Colorimetry (chemical method)|colorimetric]] enzyme reaction measures cholesterol in the non-blocked HDL particles.<ref>{{cite journal | vauthors = Warnick GR, Nauck M, Rifai N | title = Evolution of methods for measurement of HDL-cholesterol: from ultracentrifugation to homogeneous assays | journal = Clinical Chemistry | volume = 47 | issue = 9 | pages = 1579–1596 | date = Sep 2001 | doi = 10.1093/clinchem/47.9.1579 | pmid = 11514391 | url = http://www.clinchem.org/content/47/9/1579.full | access-date = 2013-11-10 | archive-url = https://web.archive.org/web/20140313071220/http://www.clinchem.org/content/47/9/1579.full | archive-date = 2014-03-13 | url-status = dead | doi-access = free }}</ref> [[High-performance liquid chromatography|HPLC]] can also be used.<ref>{{cite journal | vauthors = Okazaki M, Sasamoto K, Muramatsu T, Hosaki S | title = Evaluation of precipitation and direct methods for HDL-cholesterol assay by HPLC | journal = Clinical Chemistry | volume = 43 | issue = 10 | pages = 1885–90 | date = Oct 1997 | doi = 10.1093/clinchem/43.10.1885 | pmid = 9342008 | url = http://www.clinchem.org/cgi/content/abstract/43/10/1885 | access-date = 2009-10-08 | archive-url = https://web.archive.org/web/20080724115339/http://www.clinchem.org/cgi/content/abstract/43/10/1885 | archive-date = 2008-07-24 | url-status = dead | doi-access = free }}</ref> Subfractions (HDL-2C, HDL-3C) can be measured,<ref>{{cite journal | vauthors = Hirano T, Nohtomi K, Koba S, Muroi A, Ito Y | title = A simple and precise method for measuring HDL-cholesterol subfractions by a single precipitation followed by homogenous HDL-cholesterol assay | journal = Journal of Lipid Research | volume = 49 | issue = 5 | pages = 1130–6 | date = May 2008 | pmid = 18223297 | doi = 10.1194/jlr.D700027-JLR200 | doi-access = free }}</ref> but clinical significance of these subfractions has not been determined.<ref name="pmid23312047">{{cite journal | vauthors=Superko HR, Pendyala L, Williams PT, Momary KM, King SB 3rd, Garrett BC | title=High-density lipoprotein subclasses and their relationship to cardiovascular disease | journal=[[Journal of Clinical Lipidology]] | volume=6 | issue=6 | year=2012 | pages=496–523 | doi = 10.1016/j.jacl.2012.03.001 | pmid=23312047}}</ref>  The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate.{{citation needed|date=March 2021}}

=== Recommended ranges ===
The [[American Heart Association]], [[NIH]] and [[National Cholesterol Education Program|NCEP]] provide a set of guidelines for fasting HDL levels and risk for [[Coronary heart disease|heart disease]].<ref>{{cite web
| url=http://www.americanheart.org/presenter.jhtml?identifier=4500
| title=Cholesterol Levels
| publisher=American Heart Association
| access-date=14 November 2009
| archive-url=https://web.archive.org/web/20100208054234/http://www.americanheart.org/presenter.jhtml?identifier=4500
| archive-date=8 February 2010
}}</ref><ref>{{cite web
| url=http://www.americanheart.org/downloadable/heart/119618151049911%20CholLevels%209_07.pdf
| title=What Do My Cholesterol Levels Mean?
| publisher=American Heart Association
|date = September 2007| access-date=14 November 2009
| archive-url=https://web.archive.org/web/20081203122456/http://www.americanheart.org/downloadable/heart/119618151049911%20CholLevels%209_07.pdf
| archive-date=3 December 2008
}}</ref><ref>{{cite web
|url=http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf
|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
|date=May 2001
|work=National Heart, Lung, and Blood Institute (NHLBI)
|publisher=National Institutes of Health
|access-date=2009-12-03
|archive-date=2009-08-02
|archive-url=https://web.archive.org/web/20090802002640/http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf
|url-status=live
}}</ref>

{| class="wikitable"
|-
! Level mg/dL
! Level [[Mole (unit)|mmol]]/L
! Interpretation
|-
| <40 (men), <50 (women)
| <1.03 (men), <1.29 (women)
| Low HDL cholesterol, considered correlated for heart disease (heightened risk)
|-
| 40–59 (men), 50–59 (women)
| 1.03–1.55 (men), 1.29–1.55 (women)
| Medium HDL level
|-
| >59
| >1.55
| High HDL level, optimal condition considered correlated against heart disease
|}
High LDL with low HDL level is an additional risk factor for cardiovascular disease.<ref>ASHWOOD, E. R., BURTIS, C. A., & BRUNS, D. E. (2008). Tietz fundamentals of clinical chemistry. (6th ed., p. 415). St. Louis, MO: Saunders Elsevier.</ref>

== Measuring HDL concentration and sizes ==
As technology has reduced costs and clinical trials have continued to demonstrate the importance of HDL,<ref>{{Cite journal |last=Gotto |first=Antonio M |date=September 1999 |title=Importance of HDL from recent clinical trials: how good is the evidence? |url=https://www.atherosclerosis-journal.com/article/S0021-9150(99)00235-X/fulltext |journal=Atherosclerosis |volume=146 |pages=S17–S18 |doi=10.1016/S0021-9150(99)00235-X |doi-access=free }}</ref> methods for directly measuring HDL concentrations and size (which indicates function) at lower costs have become more widely available and increasingly regarded as important for assessing individual risk for progressive [[atherosclerosis|arterial disease]] and treatment methods.{{citation needed|date=March 2023}}

=== Electrophoresis measurements ===
Since the HDL particles have a net negative charge and vary by density & size, ultracentrifugation combined with [[electrophoresis]] have been utilized since before 1950 to enumerate the concentration of HDL particles and sort them by size with a specific volume of blood plasma. Larger HDL particles are carrying more cholesterol.

=== NMR measurements ===
Concentration and sizes of lipoprotein particles can be estimated using [[nuclear magnetic resonance]] fingerprinting.<ref name="pmid17110242">{{cite journal | vauthors = Jeyarajah EJ, Cromwell WC, Otvos JD | title = Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy | journal = Clin. Lab. Med. | volume = 26 | issue = 4 | pages = 847–70 | year = 2006 | pmid = 17110242 | doi = 10.1016/j.cll.2006.07.006 }}</ref>

==== Optimal total and large HDL concentrations ====
The HDL particle concentrations are typically categorized by event rate percentiles based on the people participating and being tracked in the MESA<ref>{{Cite web |url=http://www.mesa-nhlbi.org/ |title=mesa-nhlbi.org |access-date=2016-12-07 |archive-date=2016-12-15 |archive-url=https://web.archive.org/web/20161215100947/https://www.mesa-nhlbi.org/ |url-status=live }}</ref> trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.

{| class="wikitable"
|+ Total HDL particle Table
! MESA Percentile
! Total HDL particles [[mole (unit)|μmol]]/L
! Interpretation
|-
| >75%
| >34.9
| Those with highest (Optimal) total HDL particle concentrations & lowest rates of cardiovascular disease events
|-
| 50–75%
| 30.5–34.5
| Those with moderately high total HDL particle concentrations & moderate rates of cardiovascular disease events
|-
| 25–50%
| 26.7–30.5
| Those with lower total HDL particle concentrations & Borderline-High rates of cardiovascular disease
|-
| 0–25%
| <26.7
| Those with lowest total HDL particle concentrations & Highest rates of cardiovascular disease events
|}

{| class="wikitable"
|+ Large (protective) HDL particle Table
! MESA Percentile
! Large HDL particles [[mole (unit)|μmol]]/L
! Interpretation
|-
| >75%
| >7.3
| Those with highest (Optimal) Large HDL particle concentrations & lowest rates of cardiovascular disease events
|-
| 50–75%
| 4.8–7.3
| Those with moderately high Large HDL particle concentrations & moderate rates of cardiovascular disease events
|-
| 25–50%
| 3.1–4.8
| Those with lower Large HDL particle concentrations & Borderline-High rates of cardiovascular disease
|-
| 0–25%
| <3.1
| Those with lowest Large HDL particle concentrations & Highest rates of cardiovascular disease events
|}

The lowest incidence of atherosclerotic events over time occurs within those with both the highest concentrations of total HDL particles (the top quarter, >75%) and the highest concentrations of large HDL particles. Multiple additional measures, including LDL particle concentrations, small LDL particle concentrations, VLDL concentrations, estimations of [[insulin resistance]] and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are routinely provided in clinical testing.

== Increasing HDL levels ==

While higher HDL levels are correlated with lower risk of cardiovascular diseases, no medication used to increase HDL has been proven to improve health.<ref name=deng/><ref>{{cite journal|vauthors=Keene D, Price C, Shun-Shin MJ, Francis DP|date=Jul 18, 2014|title=Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients|journal=BMJ|volume=349|pages=g4379|doi=10.1136/bmj.g4379|pmc=4103514|pmid=25038074}}</ref> As of 2017, numerous lifestyle changes and drugs to increase HDL levels were under study.<ref name=deng/>

HDL lipoprotein particles that bear [[apolipoprotein C3]] are associated with increased, rather than decreased, risk for [[coronary heart disease]].<ref name="pmid21421846">{{cite journal | vauthors=Sacks FM, Zheng C, Cohn JS | title=Complexities of plasma apolipoprotein C-III metabolism | journal= [[Journal of Lipid Research]] | volume=52 | issue=6 | pages=1067–1070 | year=2011 | doi= 10.1194/jlr.E015701  |doi-access=free |pmid = 21421846| pmc=3090227 }}</ref>

=== Diet and exercise ===
Certain changes in diet and exercise may have a positive impact on raising HDL levels:<ref>{{cite web |first=Richard N. |last=Fogoros |date=15 September 2009 |url=http://heartdisease.about.com/cs/cholesterol/a/raiseHDL.htm |title=Raising Your HDL Levels Increasing the GOOD cholesterol |publisher=[[About.com]] |access-date=8 October 2009 |archive-date=14 July 2006 |archive-url=https://web.archive.org/web/20060714074213/http://heartdisease.about.com/cs/cholesterol/a/raiseHDL.htm |url-status=live }}</ref>
* Decreased intake of [[simple carbohydrates]].<ref>{{cite journal |url=http://www.ajcn.org/content/77/5/1146.full |title=Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials |date=2003 |publisher=Ajcn.org |doi=10.1093/ajcn/77.5.1146 |access-date=2015-11-05 |archive-date=2012-08-14 |archive-url=https://web.archive.org/web/20120814062117/http://www.ajcn.org/content/77/5/1146.full |url-status=live |last1=Mensink |first1=Ronald P. |last2=Zock |first2=Peter L. |last3=Kester |first3=Arnold DM |last4=Katan |first4=Martijn B. |journal=The American Journal of Clinical Nutrition |volume=77 |issue=5 |pages=1146–1155 |pmid=12716665 }}</ref><ref>{{cite journal | vauthors = Ma Y, Li Y, Chiriboga DE, Olendzki BC, Hebert JR, Li W, Leung K, Hafner AR, Ockene IS | title = Association between carbohydrate intake and serum lipids | journal = Journal of the American College of Nutrition | volume = 25 | issue = 2 | pages = 155–163 | date = Apr 2006 | pmid = 16582033 | pmc = 1479303 | doi = 10.1080/07315724.2006.10719527 | url = http://www.jacn.org/content/25/2/155.full | access-date = 2012-09-01 | archive-url = https://web.archive.org/web/20120115141928/http://www.jacn.org/content/25/2/155.full | archive-date = 2012-01-15 | url-status = dead }}</ref><ref name="pmid20089734">{{cite journal | vauthors = Siri-Tarino PW, Sun Q, Hu FB, Krauss RM | title = Saturated fat, carbohydrate, and cardiovascular disease | journal = The American Journal of Clinical Nutrition | volume = 91 | issue = 3 | pages = 502–9 | date = Mar 2010 | pmid = 20089734 | pmc = 2824150 | doi = 10.3945/ajcn.2008.26285 }}</ref><ref>{{cite journal | vauthors = Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT | title = Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia | journal = The American Journal of Clinical Nutrition | volume = 83 | issue = 5 | pages = 1025–1031 | date = May 2006 | pmid = 16685042 | doi = 10.1093/ajcn/83.5.1025 | doi-access = free }}</ref>
* [[Aerobic exercise]]<ref>{{cite journal | vauthors = Spate-Douglas T, Keyser RE | title = Exercise intensity: its effect on the high-density lipoprotein profile | journal = Archives of Physical Medicine and Rehabilitation | volume = 80 | issue = 6 | pages = 691–5 | date = Jun 1999 | pmid = 10378497 | doi = 10.1016/S0003-9993(99)90174-0 }}</ref>
* [[Weight loss]]<ref name=Hausenloy>{{cite journal | vauthors = Hausenloy DJ, Yellon DM | title = Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels | journal = Heart | volume = 94 | issue = 6 | pages = 706–14 | date = Jun 2008 | pmid = 18480348 | doi = 10.1136/hrt.2007.125401 | s2cid = 743920 }}</ref>
* [[Avocado]] consumption<ref name=Avocado>{{cite journal | vauthors = Mahmassani HA, Avendano EE, Raman G, Johnson EJ | title = Avocado consumption and risk factors for heart disease: a systematic review and meta-analysis | journal = The American Journal of Clinical Nutrition | volume = 107 | issue = 4 | pages = 523–536 | date = April 2018 | pmid = 29635493 | doi = 10.1093/ajcn/nqx078 | doi-access = free }}</ref>
* [[Magnesium]] supplements raise HDL-C.<ref>{{cite journal | vauthors = Rosanoff A, Seelig MS | title = Comparison of mechanism and functional effects of magnesium and statin pharmaceuticals | journal = Journal of the American College of Nutrition | volume = 23 | issue = 5 | pages = 501S–505S | date = Oct 2004 | pmid = 15466951 | doi = 10.1080/07315724.2004.10719389 | s2cid = 13156080 | url = http://www.jacn.org/cgi/content/full/23/5/501S | quote = HMG CoA Reductase is an important enzyme in lipid and cholesterol metabolism, but it is not the only one. The statins act by inhibiting, temporarily, the enzyme, in a dose response relationship whereas the magnesium ion (Mg2+) is an important part of a complex control and regulation of this important pathway. Both lower LDL-C, some statins can raise HDL-C and lower triglycerides, but Mg supplements do both quite reliably. | access-date = 2010-12-13 | archive-url = https://web.archive.org/web/20100831123037/http://www.jacn.org/cgi/content/full/23/5/501S | archive-date = 2010-08-31 | url-status = dead }}</ref>
* Addition of [[Dietary fiber|soluble fiber]] to diet<ref name="pmid12772818">{{cite journal | vauthors = Hermansen K, Dinesen B, Hoie LH, Morgenstern E, Gruenwald J | title = Effects of soy and other natural products on LDL:HDL ratio and other lipid parameters: a literature review | journal = Advances in Therapy | volume = 20 | issue = 1 | pages = 50–78 | year = 2003 | pmid = 12772818 | doi =  10.1007/bf02850119| s2cid = 41025973 }}</ref>
* Consumption of [[omega-3 fatty acids]] such as fish oil<ref>{{cite web |publisher=The Cleveland Clinic Heart and Vascular Institute |url=http://my.clevelandclinic.org/heart/prevention/nutrition/omega3.aspx |access-date=8 October 2009 |title=The Power of Fish |archive-date=17 September 2009 |archive-url=https://web.archive.org/web/20090917064308/http://my.clevelandclinic.org/heart/prevention/nutrition/omega3.aspx |url-status=live }}</ref> or [[Linseed oil#Nutritional supplement|flax oil]]<ref>{{cite web|website=WebMD|url=http://www.webmd.com/vitamins-and-supplements/lifestyle-guide-11/supplement-guide-flaxseed-oil|access-date=12 August 2013|title=Vitamins and Supplements Lifestyle Guide – Flaxseed|archive-date=9 June 2016|archive-url=https://web.archive.org/web/20160609151643/http://www.webmd.com/vitamins-and-supplements/lifestyle-guide-11/supplement-guide-flaxseed-oil|url-status=live}}</ref>
* Increased intake of [[unsaturated fat]]s<ref>{{cite journal | vauthors = Mensink RP, Zock PL, Kester AD, Katan MB | title = Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials | journal = The American Journal of Clinical Nutrition | volume = 77 | issue = 5 | pages = 1146–55 | date = May 2003 | pmid = 12716665 | doi=10.1093/ajcn/77.5.1146| doi-access = free }}</ref>
* Removal of [[trans fat]]ty acids from the diet<ref>{{cite web | title = Trans fat: Avoid this cholesterol double whammy | publisher = Mayo Foundation for Medical Education and Research (MFMER) | url = https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/trans-fat/art-20046114 | access-date = 25 June 2010 | archive-date = 6 January 2014 | archive-url = https://web.archive.org/web/20140106204835/http://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/trans-fat/ART-20046114 | url-status = live }}</ref>

Most [[saturated fats]] increase HDL cholesterol to varying degrees but also raise total and LDL cholesterol.<ref name=Thijssen>{{cite book|last1=Thijssen |first1=M. A. |first2=R. P. |last2=Mensink |year=2005 |chapter-url=https://books.google.com/books?id=kvo6BN1AGNAC&pg=PA171 |chapter=Fatty Acids and Atherosclerotic Risk |archive-url=https://web.archive.org/web/20191025184653/https://books.google.com/books?id=kvo6BN1AGNAC&pg=PA171#v=onepage |archive-date=2019-10-25 |editor-first=Arnold |editor-last=von Eckardstein |title=Atherosclerosis: Diet and Drugs |publisher=Springer |pages=171–172 |isbn=978-3-540-22569-0}}</ref>

=== Recreational drugs ===
HDL levels can be increased by [[smoking cessation]],<ref name=Hausenloy /> or mild to moderate [[Alcohol and cardiovascular disease|alcohol]] intake.<ref>{{cite journal | vauthors = Baer DJ, Judd JT, Clevidence BA, Muesing RA, Campbell WS, Brown ED, Taylor PR | title = Moderate alcohol consumption lowers risk factors for cardiovascular disease in postmenopausal women fed a controlled diet | journal = The American Journal of Clinical Nutrition | volume = 75 | issue = 3 | pages = 593–599 | date = Mar 2002 | pmid = 11864868 | doi=10.1093/ajcn/75.3.593| doi-access = free }}</ref><ref>{{cite journal | vauthors = van der Gaag MS, van Tol A, Vermunt SH, Scheek LM, Schaafsma G, Hendriks HF | title = Alcohol consumption stimulates early steps in reverse cholesterol transport | journal = Journal of Lipid Research | volume = 42 | issue = 12 | pages = 2077–2083 | date = Dec 2001 | doi = 10.1016/S0022-2275(20)31537-6 | pmid = 11734581 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hendriks HF, Veenstra J, van Tol A, Groener JE, Schaafsma G | title = Moderate doses of alcoholic beverages with dinner and postprandial high density lipoprotein composition | journal = Alcohol and Alcoholism | volume = 33 | issue = 4 | pages = 403–410 | year = 1998 | pmid = 9719399 | doi = 10.1093/oxfordjournals.alcalc.a008410 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Clevidence BA, Reichman ME, Judd JT, Muesing RA, Schatzkin A, Schaefer EJ, Li Z, Jenner J, Brown CC, Sunkin M | title = Effects of alcohol consumption on lipoproteins of premenopausal women. A controlled diet study | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 15 | issue = 2 | pages = 179–184 | date = Feb 1995 | pmid = 7749823 | doi = 10.1161/01.ATV.15.2.179 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cuvelier I, Steinmetz J, Mikstacki T, Siest G | title = Variations in total phospholipids and high-density lipoprotein phospholipids in plasma from a general population: reference intervals and influence of xenobiotics | journal = Clinical Chemistry | volume = 31 | issue = 5 | pages = 763–766 | date = May 1985 | doi = 10.1093/clinchem/31.5.763 | pmid = 3987006 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brenn T | title = The Tromsø heart study: alcoholic beverages and coronary risk factors | journal = Journal of Epidemiology and Community Health | volume = 40 | issue = 3 | pages = 249–256 | date = Sep 1986 | pmid = 3772283 | pmc = 1052533 | doi = 10.1136/jech.40.3.249 }}</ref>

[[Cannabis (drug)|Cannabis]] in unadjusted analyses, past and current cannabis use was not associated with higher HDL-C levels.<ref name="Penner" />  A study performed in 4635 patients demonstrated no effect on the HDL-C levels (P=0.78) [the mean (standard error) HDL-C values in control subjects (never used), past users and current users were 53.4 (0.4), 53.9 (0.6) and 53.9 (0.7) mg/dL, respectively].<ref name="Penner">{{cite journal | vauthors = Penner EA, Buettner H, Mittleman MA | title = The impact of marijuana use on glucose, insulin, and insulin resistance among US adults | journal = The American Journal of Medicine | volume = 126 | issue = 7 | pages = 583–9 | date = Jul 2013 | pmid = 23684393 | doi = 10.1016/j.amjmed.2013.03.002 | doi-access = free }}</ref>

Exogenous [[anabolic androgenic steroids]], particularly [[17α-alkylated anabolic steroid]]s and others administered orally, can reduce HDL-C by 50 percent or more.<ref>{{cite journal |last1=Rader |first1=Daniel J. |last2=deGoma |first2=Emil M. |title=Approach to the Patient with Extremely Low HDL-Cholesterol |journal=The Journal of Clinical Endocrinology & Metabolism |date=October 2012 |volume=97 |issue=10 |pages=3399–3407 |doi=10.1210/jc.2012-2185 |pmid=23043194 |doi-access=free |pmc=3462950 }}</ref> Other [[androgen receptor]] agonists such as [[selective androgen receptor modulators]] can also lower HDL. As there is some evidence that the HDL reduction is caused by increased [[reverse cholesterol transport]], it is unknown if AR agonists' HDL-lowering effect is pro- or anti-[[atherogenic]].<ref>{{cite journal |last1=Choi |first1=Seul Min |last2=Lee |first2=Byung-Mu |title=Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids |journal=Expert Opinion on Drug Safety |date=2 November 2015 |volume=14 |issue=11 |pages=1773–1785 |doi=10.1517/14740338.2015.1094052|pmid=26401842 |s2cid=8104778 }}</ref>

=== Pharmaceutical drugs and niacin ===

[[Pharmacological therapy]] to increase the level of HDL cholesterol includes use of [[fibrate]]s and [[Niacin (substance)|niacin]]. Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids.<ref>{{cite journal | vauthors = Benatar JR, Stewart RA | title = Is it time to stop treating dyslipidaemia with fibrates? | journal = The New Zealand Medical Journal | volume = 120 | issue = 1261 | pages = U2706 | year = 2007 | pmid = 17853928 | url = http://www.nzma.org.nz/journal/120-1261/2706/ | access-date = 2009-04-29 | archive-url = https://web.archive.org/web/20090706005219/http://www.nzma.org.nz/journal/120-1261/2706/ | archive-date = 2009-07-06 | url-status = dead }}</ref>

[[Niacin (substance)|Niacin]] (nicotinic acid, a form of [[vitamin B3]]) increases HDL 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 | title = Niacin therapy in atherosclerosis | journal = Current Opinion in Lipidology | volume = 15 | issue = 6 | pages = 659–65 | date = Dec 2004 | pmid = 15529025 | doi = 10.1097/00041433-200412000-00006 }}</ref> otherwise known as  [[niacin receptor 2]] and HM74A / GPR109A,<ref name="ReferenceA">{{cite journal | vauthors = Soudijn W, van Wijngaarden I, Ijzerman AP | title = Nicotinic acid receptor subtypes and their ligands | journal = Medicinal Research Reviews | volume = 27 | issue = 3 | pages = 417–33 | date = May 2007 | pmid = 17238156 | doi = 10.1002/med.20102 | s2cid = 20876888 }}</ref> [[niacin receptor 1]].

Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%,<ref>{{cite web |url=http://cme.medscape.com/viewarticle/479499_5 |access-date=8 October 2009 |title=Raising HDL in Clinical Practice |work=Raising HDL in Clinical Practice: Clinical Strategies to Elevate HDL |first=Daniel J. |last=Rader |year=2004 |archive-date=12 September 2019 |archive-url=https://web.archive.org/web/20190912024737/https://login.medscape.com/login/sso/getlogin?urlCache=aHR0cHM6Ly93d3cubWVkc2NhcGUub3JnL3ZpZXdhcnRpY2xlLzQ3OTQ5OV81&ac=401 |url-status=live }}</ref> making it the most powerful agent to increase HDL-cholesterol.<ref name="rhcrcr">{{cite web |title=Raising HDL-Cholesterol and Reducing Cardiovascular Risk: An Expert Interview With H. Bryan Brewer, Jr, MD |url=http://cme.medscape.com/viewarticle/520393 |access-date=8 October 2009 |first=H. Bryan |last=Brewer |date=27 December 2005 |archive-date=12 September 2019 |archive-url=https://web.archive.org/web/20190912024716/https://login.medscape.com/login/sso/getlogin?urlCache=aHR0cHM6Ly93d3cubWVkc2NhcGUub3JnL3ZpZXdhcnRpY2xlLzUyMDM5Mw==&ac=401 |url-status=live }}</ref><ref>{{cite journal | vauthors = Chapman MJ, Assmann G, Fruchart JC, Shepherd J, Sirtori C, ((European Consensus Panel on HDL-C)) | title = Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid—a position paper developed by the European Consensus Panel on HDL-C | journal = Current Medical Research and Opinion | volume = 20 | issue = 8 | pages = 1253–68 | date = Aug 2004 | pmid = 15324528 | doi = 10.1185/030079904125004402 | s2cid = 1009560 }}</ref> A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events.<ref name="ehjs">{{Cite journal|doi=10.1093/eurheartj/sul037 |title=Reducing risk by raising HDL-cholesterol: the evidence |year=2006 |last1=Drexel |first1=H. |journal=European Heart Journal Supplements |volume=8 |pages=F23–F29|doi-access=free }}</ref> Niacin products sold as "no-flush", ''i.e.'' not having side-effects such as "niacin [[Flushing (physiology)|flush]]", do not, however, contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation.<ref>{{cite journal | vauthors = Meyers CD, Carr MC, Park S, Brunzell JD | title = Varying cost and free nicotinic acid content in over-the-counter niacin preparations for dyslipidemia | journal = Annals of Internal Medicine | volume = 139 | issue = 12 | pages = 996–1002 | date = Dec 2003 | pmid = 14678919 | doi = 10.7326/0003-4819-139-12-200312160-00009 | s2cid = 23980567 }}</ref> Both fibrates and niacin increase artery toxic [[homocysteine]], an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, but multiple European trials of the most popular B-vitamin cocktails, trial showing 30% average reduction in homocysteine, while not showing problems have also not shown any benefit in reducing cardiovascular event rates.  A 2011 extended-release niacin (Niaspan) study was halted early because patients adding niacin to their statin treatment showed no increase in heart health, but did experience an increase in the risk of stroke.<ref>{{cite web |url=https://www.npr.org/blogs/health/2011/05/28/136678665/study-boosting-good-cholesterol-with-niacin-did-not-cut-heart-risks?ps=sh_sthdl |title=Study: Boosting Good Cholesterol With Niacin Did Not Cut Heart Risks : Shots – Health News |publisher=NPR |date=2011-05-26 |access-date=2015-11-05 |archive-date=2015-03-27 |archive-url=https://web.archive.org/web/20150327121026/http://www.npr.org/blogs/health/2011/05/28/136678665/study-boosting-good-cholesterol-with-niacin-did-not-cut-heart-risks?ps=sh_sthdl |url-status=live }}</ref>

In contrast, while the use of [[statin]]s is effective against high levels of [[Low-density lipoprotein|LDL]] cholesterol, most have little or no effect in raising HDL cholesterol.<ref name="rhcrcr" /> [[Rosuvastatin]] and [[pitavastatin]], however, have been demonstrated to significantly raise HDL levels.<ref>{{cite web|url=http://www.cholesteroladvice.net/treatment-high-cholesterol-level/ |title=When is treatment indicated for high cholesterol level? |url-status=dead |archive-url=https://web.archive.org/web/20120730073614/http://www.cholesteroladvice.net/treatment-high-cholesterol-level/ |archive-date=30 July 2012 |df=dmy }}</ref>

[[Lovaza]] has been shown to increase HDL-C.<ref>[http://us.gsk.com/products/assets/us_lovaza.pdf]  {{webarchive|url=https://web.archive.org/web/20120301074136/http://us.gsk.com/products/assets/us_lovaza.pdf|date=1 March 2012}}</ref> However, the best evidence to date suggests it has no benefit for primary or secondary prevention of cardiovascular disease.

The [[peroxisome proliferator-activated receptor|PPAR]] modulator [[GW501516]] has shown a positive effect on HDL-C<ref>{{Cite journal|title=Effects of peroxisome proliferator-activated receptor alpha/delta agonists on HDL-cholesterol in vervet monkeys. | pmid=15716581 | doi=10.1194/jlr.M500002-JLR200 | volume=46 | issue=5 |vauthors=Wallace JM, Schwarz M, Coward P, Houze J, Sawyer JK, Kelley KL, Chai A, Rudel LL| journal=J Lipid Res | pages=1009–16 | year=2005| doi-access=free }}</ref> and an antiatherogenic where LDL is an issue.<ref>{{Cite journal|title=Sirtuin 1 Mediates the Actions of Peroxisome Proliferator-Activated Receptor δ on the Oxidized Low-Density Lipoprotein-Triggered Migration and Proliferation of Vascular Smooth Muscle Cells. | pmid=27573670 | doi=10.1124/mol.116.104679 | volume=90 | issue=5 |vauthors=Hwang JS, Ham SA, Yoo T, Lee WJ, Paek KS, Lee CH, Seo HG| journal=Mol Pharmacol | pages=522–529 | year=2016| doi-access=free }}</ref> However, research on the drug has been discontinued after it was discovered to cause rapid cancer development in several organs in rats.<ref>{{cite conference | conference = 48th Annual Meeting of the Society of Toxicology | location = Baltimore | url = http://www.toxicology.org/AI/Pub/Tox/2009Tox.pdf | archive-url = https://web.archive.org/web/20150504013406/http://www.toxicology.org/AI/PUB/Tox/2009Tox.pdf | archive-date = 2015-05-04 | title = PS 895 - Rat carcinogenicity study with GW501516, a PPAR delta agonist | vauthors = Geiger LE, Dunsford WS, Lewis DJ, Brennan C, Liu KC, Newsholme SJ | date = 2009 | publisher = [[Society of Toxicology]] | page = 105 }}</ref><ref>{{cite conference | conference = 48th Annual Meeting of the Society of Toxicology | location = Baltimore  | url = http://www.toxicology.org/AI/Pub/Tox/2009Tox.pdf | archive-url = https://web.archive.org/web/20150504013406/http://www.toxicology.org/AI/PUB/Tox/2009Tox.pdf | archive-date = 2015-05-04 | title = PS 896 - Mouse carcinogenicity study with GW501516, a PPAR delta agonist. | vauthors = Newsholme SJ, Dunsford WS, Brodie T, Brennan C, Brown M, Geiger LE | date = 2009 | publisher = [[Society of Toxicology]] | page = 105 }}</ref>

== See also ==
* [[Asymmetric dimethylarginine]]
* [[Cardiovascular disease]]
* [[Cholesteryl ester storage disease]]
* [[Endothelium]]
* [[Lipid profile]]
* [[Lysosomal acid lipase deficiency]]

== References ==
{{Reflist}}

{{Lipoproteins}}
{{Portal bar|Biology}}

[[Category:Lipid disorders]]
[[Category:Cardiology]]
[[Category:Lipoproteins]]