ARTICLE
High Density Lipoprotein (HDL)
The Cardioprotective Lipoprotein
Garry K. Seward, Product Specialist, Thermo Fisher Scientific
This article reviews the beneficial role of high density
lipoproteins, or HDLs, to cardiovascular health. HDLs are
vital to removing excess fatty acids and lipids via the
reverse cholesterol transport pathway. Beyond this, HDL
proteins possess anti-inflammatory and anti-oxidant
activities that protect against cardiovascular disease.
HDL’s beneficial health profile has clinical relevance as well.
Small and macromolecular treatments that increase HDL
levels have been investigated as therapeutics for
cardiovascular disease. Treatments like Apo A-I Milano,
statins and fibrates can increase circulating HDL levels in
the blood and improve cardiovascular health, while others,
such as CETP inhibitors, increase circulating HDL levels in
the blood but don’t show expected improvements to
cardiac health.
The Highly Desirable Lipoprotein
Lipoproteins are macromolecular complexes that transport
lipids, fatty acids and cholesterols through the body.
Of all the lipoprotein particles, high density lipoprotein or
HDL, is the smallest and most protein-rich. In a process
called reverse cholesterol transport (RCT), HDL particles
remove excess fats and cholesterols from cells and arteries
and transport them to the liver for disposal. This unique
function gives HDL a protective role against cardiovascular
diseases, especially atherosclerosis. So while other
lipoproteins like low density lipoprotein or LDL, have
negative impacts on the cardiovascular system, HDL
generally has a favorable influence on cardiovascular health
unless it has been modified pathologically. For this reason it
is often referred to as “good” cholesterol. Indeed, research
finds that higher circulating levels of HDL are associated
with a lower risk of atherosclerotic diseases.1
Several properties help HDL convey protective effects
against atherosclerosis. HDLs primary function is promoting
cholesterol efflux from cells and delivering it to the liver and
other tissues for reuse or excretion.
For Research Use Only. Not for use in diagnostic procedures. © 2016 Thermo Fisher Scientific Inc. All rights reserved.
All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified.
Art_HighDensityLipoprotein_2016_V1
This action prevents the build-up of harmful LDL species in
blood vessels and reduces the likelihood of atherosclerotic
plaque formation.2 In addition to this function, other actions,
most notably anti-oxidant and anti-inflammatory activity
carried out by HDL proteins are also important for
atherosclerosis prevention.3 Apo A-I, which is the most
abundant protein in HDL accounting for nearly 70% of
protein mass, appears to be particularly important for the
particle’s anti-oxidant actions. Apo A-I removes oxidized
phospholipids from oxidized LDLs and also from cells.4,5
As the major HDL associated protein, it triggers cholesterol
efflux by activating transport mechanisms that remove
oxidant LDLs from the bloodstream. In addition, the protein
stabilizes antioxidant enzymes such as serum paraoxonase
(PON1) that are carried by HDL.6 And in human HDL, Apo
A-I directly reduces cholesteryl ester and
phosphatidylcholine hydroperoxides via methionine
residues 112 and 148.7
These antioxidant behaviors are essential protection
mechanisms as oxidized phospholipids and LDLs contribute
to atherosclerotic plaque formation and progression.
Apo A-II, which is the second most abundant protein in
HDL particles, makes up another 20% of the particle’s
protein mass. Its role is more elusive than that of Apo A-I,
but recent research provides evidences that it too has
anti-oxidant properties. HDL complexes enriched with Apo
A-II protect very low density lipoproteins from oxidation.7
Moreover, particles enriched with human Apo A-II are able
to promote effective reverse cholesterol transport from
macrophage cells.8 Though much of Apo A-II’s function
remains unknown, these actions indicate the importance of
Apo A-II for HDLs anti-oxidant properties.
In addition to antioxidant behavior, HDL also promotes
anti-inflammatory responses. HDL appears to neutralize
the effects of the inflammation associated C-reactive
protein (CRP).2
In vivo experiments involving administration of Apo A-I in
small animals show a reduction in inflammatory indicators
such as chemokine production and monocyte activation in
endothelial cells.6,7 HDL limits expression of cytokines such
as tumor necrosis factor-α (TNF-α) and interleukin-1 that
induce endothelial cell apoptosis and mediate the
upregulation of cell adhesion molecules.6 And in one more
piece of supporting evidence, peptide mimics of Apo A-I
have proven effective in promoting clearance of
pro-inflammatory lipids.2 These anti-inflammatory actions
are particularly important given that atherosclerosis involves
an ongoing inflammatory response within artery walls.
Clinical Relevance
Given the association between HDL levels and the lower
risk for cardiovascular disease, HDL targeting therapies
have been popular clinical interventions with varying
degrees of success. For example, reconstituted HDL has
been considered as a treatment for atherosclerosis, with
very limited success.
Reconstituted HDLs are crude lipoprotein particles,
consisting of phospholipids and apolipoproteins like Apo A-I
and Apo E. The apoproteins are inserted into phospholipid
vesicles to form bilayers containing the apolipoproteins.2
Reconstituted HDL therapies have been effective at
increasing plasma HDL levels.9 Treatment with these
particles diminishes the release of pro-inflammatory
cytokines and also reduces the expression of adhesion
molecules that would find their way into atherosclerotic
plaques.10 Unfortunately, reconstituted HDL on its own has
not yet proven an effective tool in reducing the occurrence
of coronary events, nor has it proven to be effective at
reducing the plaque burden of atherosclerotic patients.2
Apo A-I Milano, a mutant of Apo A-I, has drawn
considerable interest as a potential therapeutic due to
anti-atherogenic effects observed when administered to
small animal models. Administering Apo A-I intravenously to
rats prevented platelet aggregation and delayed formation
of blood clots.11
Intravenous administration of Apo A-I Milano also reduced
the number of atherosclerotic lesions in cholesterol fed
rabbits and led to a regression of pre-existing plaques.12
These results encouraged consideration of reconstituted
HDLs containing Apo A-I Milano mutants as a treatment in
humans, with at least one study yielding favorable results,
including rapid and significant reductions in plaques when
assessed by intravascular ultrasound.13
Gene therapies for both Apo A-I and Apo A-I Milano have
demonstrated enormous therapeutic potential in mice
models. Transgenic insertion of Apo A-I into Apo E deficient
For Research Use Only. Not for use in diagnostic procedures. © 2016 Thermo Fisher Scientific Inc. All rights reserved.
All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified.
Art_HighDensityLipoprotein_2016_V1
mice, which have an increased susceptibility to
atherosclerotic lesions, increased HDL concentrations and
dramatically reduced both the occurrence and size of
atherosclerotic lesions.14 Gene transfer of Apo A-I Milano
into Apo E knockout mice increased Apo A-I concentrations
for up to 20 weeks post therapy. It also reduced
atherosclerosis in the aorta and arteries in the head and
neck.15 Gene therapy in humans faces immense regulatory
challenges, however these studies highlight its potential for
protection against cardiovascular disease.
Small molecule treatments that increase HDL concentration
have also been considered. Inhibitors of cholesteryl ester
transfer protein (CETP) have been thoroughly investigated
for their potential as therapeutics. Deficient CETP is
associated with increased plasma HDL levels and
decreased LDL. Similarly, inhibition of CETP by small
molecules increases plasma HDL levels, while decreasing
plasma LDL concentrations.16 Several CETP inhibitors have
been investigated clinically. The most well-known is
torcetrapib, which increased HDL levels, improved Apo A-I
and –II concentrations, and also proved beneficial to lipid
metabolism.17 However, in clinical trials the treatment was
associated with increased morbidity and mortality and the
study was terminated. Other CETP inhibitors include
anacetrapib, dalcetrapib, and evacetrapib all of which are
associated with improved HDL levels and function, but have
not proven beneficial in preventing disease progression.
Anacetrapib, which has been shown to increase HDL by as
much as 138% in one study,18 is expected to remain in
clinical trials through 2017.
Trials of dalcetrapib were halted in 2012 after failing to
show any clinical efficacy and development of evacetrapib
was stopped in October of 2015 after it, too, failed to
improve clinical outcomes.
Other small molecule therapies improve HDL concentration
and function and also reduce cardiac events. Statins, which
are a widely prescribed treatment for patients with elevated
LDL, raise the levels of HDL slightly - typically in the range
of 5-10% - during treatment.2,19 Fibrates are another
treatment for patients at risk of cardiovascular diseases.
This class of agents target peroxisome proliferator-activated
receptors (PPARs), which regulate lipid metabolism and can
raise HDL by 5-20% depending on a patient’s baseline level
of HDL expression.2,3 Fenofibrate has been shown to also
increase Apo A-I.20 And fibrate therapy has proven
especially beneficial to patients that also suffer from
hyperinsulinemia or type 2 diabetes.2 Thiazolidinediones,
another class of PPAR-γ agonists also increase HDL
concentrations. These compounds increase HDL by
5-15%.2
At present though, it remains unclear whether any of these
increases in HDL are responsible for improvements in
cardiovascular health or if there are other biological actions
in vivo that improve HDL function.2,3
Niacin has proven the most effective treatment when it
comes to boosting HDL metabolism and structure. Niacin,
also known as Vitamin B3 or nicotinic acid, increases HDL
in the range of 15-35%. Niacin also improves HDL quality. It
increases the Apo A-I residence time in HDL particles,
causing protein concentrations to rise. It also increases
HDL particle size and promotes retention of cholesteryl
esters in HDL, both of which could improve its cholesterol
efflux efficiency.2,21 Although improvements in HDL
cholesterol is well documented with niacin, there is little
clinical evidence suggesting that it also reduces the
frequency of coronary events such as heart attacks or
strokes. One study suggests that niacin resulted in rates
reduced coronary events,3,22 while another more recent
study shows no improvement in rates of cardiovascular
events after a 3 year treatment period.23
Conclusion
HDL plays an important protective role for cardiovascular
health due to its function in reverse cholesterol transport.
HDL possesses antioxidant and anti-inflammatory
properties thought to be beneficial to cardiovascular health.
Current treatments increase HDL and to various extents
protect patients from the persistent inflammation
associated with cardiovascular diseases. Furthermore,
clinical studies repeatedly show an association with
increased plasma HDL levels and reduction in
cardiovascular events, however, more definitive research is
needed to elucidate the nature of HDLs role in reducing
cardiovascular risk and improving clinical outcomes.
For Research Use Only. Not for use in diagnostic procedures. © 2016 Thermo Fisher Scientific Inc. All rights reserved.
All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified.
Art_HighDensityLipoprotein_2016_V1
References
1.
2.
Boden WE. High-density lipoprotein cholesterol as an independent
10. Spieker LE,; Sudano I,; Hurlimann D,; Lerch PG,; Lang MG,; Binggeli
risk factor in cardiovascular disease: Assessing the data from
C, Corti R,; Ruschitzka F,; Lüscher TF,; Noll G. High-density
Framingham to the Veterans Affars High-Density Lipoprotein
lipoprotein restores endothelial function in hypercholesterolemic men.
Intervention Trial. Am J Cardiol. 2000, 19L–22L.
Circulation 2002, 105, 1399–1402.
Otocka-Kmiecik A,; Mikhailidis D.P,; Nicholls S.J,; Davidson M,; Rysz
11. Li D,; Weng S,; Yang B,; Zander DS,; Saldeen T,; Nichols WW,; et al.
J,; Banach M. Dysfuntional HDL: A novel important diagnostic and
Inhibition of arterial thrombus formation by apoA-I Milano. Arterioscler
therapeutic target in cardiovascular disease? Prog Lipid Res. 2012,
Thromb Vasc Biol. 1999, 19, 378–383.
51, 314–324.
12. Ameli S,; Hultgardh-Nilsson A,; Cercek B,; Shah PK,; Forrester J,;
3.
4.
Duffy D,; Rader D.J. Emerging Therapies Targeting High-Density
Ageland H,; et al. Recombinant apolipoprotein A-1 Milano reduces
Lipoprotein Metabolism and Reverse Cholesterol Transport.
intimal thickening after balloon injury in hypercholesterolemic rabbits.
Circulation. 2006, 113, 1140–1150.
Circulation. 1994, 90, 1935–1941.
Navab M,; Hama S.Y,; Cooke C.J,; Anantharamaiah G.M,; Chaddha
13. Nissen SE,; Tsunoda T,; Tuzcu EM,; Schoenhagen P,; Cooper CJ,;
M,; Jin L,; Subbanagounder G,; Faull K.F,; Reddy S.T,; Miller N.E,;
Yasin M,; et al. Effect of recombinant ApoA-I Milano on coronary
Fogelman A.M. Normal high density lipoprotein inhibits three steps in
atherosclerosis in patients with acute coronary syndromes: A
the formation of mildly oxidized low density lipoprotein: Step 1. J Lipid
randomized controlled trial. JAMA. 2003, 290, 2292–2300.
Res. 2000, 41,1481–1494.
14. Paszty C,; Maeda N,; Verstuyft J,; Rubin EM. Apolipoprotein AI
5.
Navab M,; Hama SY,; Anantharamaiah GM,; Hassan K,; Hough GP,;
transgene corrects apolipoprotein E deficiency-induced atheroclerosis
Watson AD,; Reddy ST,; Sevanian A,; Fonarow GC,; Fogelman A.M.
in mice. J Clin Invest. 1994, 94, 899–903.
Normal high density lipoprotein inhibits three steps in the formation of
mildly oxidized low density lipoprotein: Steps 2 and 3. J Lipid Res.
2000, 41,1495–1508.
15. Tian F,; Wang L,; Arias A,; Yang M,; Sharifi BG,; Shah PK.
Comparative antiatherogenic effects of intravenous AAV8- and
AAV2-mediated apoA-IMilano gene transfer in hypercholesterolemic
6.
Birner-Gruenberger R,; Schittmayer M,; Holzer M,; Marsche G.
mice. J Cardiovasc Pharmcol Ther. 2015, 20, 66–75.
Understanding high-density lipoprotein function in disease: Recent
advances in proteomics unravel the complexity of its composition and
biology. Prog Lipid Res. 2014, 56, 36–46.
16. Le Goff W,; Guerin M. And Chapman MJ Pharmacological modulation
of cholesteryl ester transfer protein, a new therapeutic target in
atherogenic dyslipidemia. Pharmacol Ther. 2004, 101, 17–38.
7.
Podrez EA. Anti-Oxidant properties of high-density lipoprotein and
atherosclerosis. Clin Exp Pharmacol Physiol. 2010, 37(7), 719–725.
17. Brousseau ME,; Schaefer EJ,; Wolfe ML,; Bloedon LT,; Digenio AG,;
Clark RW,; et al. Effects of an inhibitor of cholesteryl ester transfer
8.
Boisfer E,; Stengel D,; Pastier D,; Laplaud PM,; Dousset N,; Ninio E,;
protein on HDL cholesterol. N Engl J Med. 2004, 350, 1505–1515.
Kalopissis A-D. Antioxidant properties of HDL in transgenic mice
overexpressing human apolipoprotein A-II. J Lipid Res. 2002, 43,
732–741.
18. Cannon CP,; Shah S,; Dansky HM,; Davidson M,; Brinton EA,; Gotto
AM,; et al. Determining the efficacy and tolerability investigators.
Safety of anacetrapib in patients with or at high risk for coronary heart
9.
Ryan RO. Nanobiotechnology applications of reconstituted high
disease. N Engl J Med. 2010, 363, 2406–2415.
density lipoprotein. J Nanobiotechnol. 2010, 8, 28.
For Research Use Only. Not for use in diagnostic procedures. © 2016 Thermo Fisher Scientific Inc. All rights reserved.
All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified.
Art_HighDensityLipoprotein_2016_V1
19. Downs JR,; Clearfield M,; Weis S,; Whitney E,; Shapiro DR,; Beere
PA,; Langendorfer A,; Stein EA,; Kruyer W,; Gotto AM Jr. Primary
prevention of acute coronary events with lovastatin in men and
women with average cholesterol levels: results of AFCAPS/TexCAPS.
Air Force/Texa coronary atherosclerosis prevention study. JAMA.
1998, 279, 1615–1622.
20. Despres JP,; Lemieux I,; Robins SJ. Role of fibric acid derivatives in
the management of risk factors for coronary heart disease. Drugs.
2004, 64, 2177–2198.
21. Sakai T,; Kamanna VS,; Kashyap ML. Niacin, but not gemfibrozil,
selectively increases LPAI, a cardioprotective subfraction of HDL,
in patients with low HDL cholesterol. Arterioscler Thromb Vasc Biol.
2001, 21, 73–79.
22. Canner PL,; Berge KG,; Wenger NK,; Stamler J,; Friedman L,; Prineas
RJ,; Friedewald W. Fifteen year mortality in Coronary Drug Project
patients: long-term benefit with niacin. J Am Coll Cardiol. 1986,
8,1245–1255
23. AIM–HIGH Investigators,; Boden WE,; Probstfield JL,; Anderson T,; et
al. Niacin in patients with low HDL cholesterol levels receiving
intensive statin therapy. N Engl J Med. 2011, 365, 2255–2267.
For Research Use Only. Not for use in diagnostic procedures. © 2016 Thermo Fisher Scientific Inc. All rights reserved.
All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified.
Art_HighDensityLipoprotein_2016_V1
Order our products online www.alfa.com
For Research Use Only. Not for use in diagnostic procedures. © 2016 Thermo Fisher Scientific Inc. All rights reserved.
All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified.
Art_HighDensityLipoprotein_2016_V1