Physical Fitness and Reverse Cholesterol Transport
Beata Olchawa, Bronwyn A. Kingwell, Anh Hoang, Laurence Schneider, Osamu Miyazaki,
Paul Nestel, Dmitri Sviridov
Downloaded from http://atvb.ahajournals.org/ by guest on June 14, 2017
Background—Physical exercise is associated with a decreased risk of cardiovascular disease, which may be partly caused
by the effect of exercise on the lipoprotein profile. The most consistent effect of exercise on lipoprotein metabolism is
an increase in high-density lipoprotein (HDL).
Methods and Results—Parameters of reverse cholesterol transport (RCT) in 25 endurance-trained male athletes were
compared with 33 age-matched males enjoying an active lifestyle. VO2max was higher in athletes than in controls
(53.4⫾1.2 versus 38.8⫾1.0 mL/min per kg; P⬍0.01). The following differences in parameters of RCT were found: (1)
plasma HDL cholesterol and apoA-I levels were higher in athletes compared with controls (1.7⫾0.1 versus
1.4⫾0.1 mmol/L; P⬍0.001; and 145⫾2 versus 128⫾3 mg/dL; P⬍0.001, respectively). Both correlated with VO2max
up to the value of 51 mL/min per kg; (2) pre␤1-HDL was higher in athletes than in controls (54⫾4 versus 37⫾3 ␮g/mL;
P⬍0.001) and correlated positively with VO2max; (3) lecithin cholesterol: acyltransferase activity was higher in athletes
(29.8⫾1.2 versus 24.2⫾1.4 nmol/␮L per hour; P⬍0.005); and (4) the capacity of plasma to promote cholesterol efflux
from macrophages was higher in athletes (18.8%⫾0.8% versus 16.2%⫾0.3%; P⬍0.03).
Conclusions—The likely reason for higher HDL concentration in physically fit people is increased formation of HDL from
apoA-I and cellular lipids. (Arterioscler Thromb Vasc Biol. 2004;24:1087-1091.)
Key Words: atherosclerosis 䡲 lipoproteins 䡲 exercise 䡲 cholesterol
P
hysical exercise and fitness are considered key factors
affecting overall risk of cardiovascular disease. It is an
effective intervention for prevention and treatment of coronary artery disease (CAD) as well as for rehabilitation of
coronary patients.1,2 Exercise favorably affects a number of
cardiovascular risk factors, such as obesity, insulin resistance,
and blood pressure; it also has a beneficial effect on the
lipoprotein profile.3–5 The latter may be a significant contributor to the protective effect of exercise partly by lowering the
concentrations of triglyceride-rich lipoprotein (TRL) and
low-density lipoprotein (LDL), especially atherogenic small
LDL.3,5 However, the most distinct and sustained effect of
exercise on lipoproteins is the increase in circulating highdensity lipoprotein (HDL), both as HDL cholesterol and the
number of HDL particles.3,5,6 These changes likely reflect
activity in the reverse cholesterol transport (RCT) pathway.
RCT is a multistep dynamic process comprising removal of
excess cholesterol from peripheral tissues, including arterial
wall macrophages and delivery to the liver for excretion.7
Although epidemiological studies consistently show that the
HDL concentration is inversely correlated with cardiovascular risk, HDL exerts a number of antiatherogenic properties8
and higher levels of HDL are not necessarily a reliable
indicator of enhanced RCT.7 To investigate the effect of
physical fitness on HDL and RCT, we studied several key
steps in RCT in endurance-trained athletes and compared
them with a reference group of physically active individuals.
We found that higher levels of physical fitness were associated with enhanced HDL formation indicating a likely increase in RCT efficiency.
Methods
Study Subjects
Twenty five male athletes were recruited from triathlon (19),
biathlon (3), running (2), and swimming (1) teams. The athletes were
23 to 42 years old (mean age: 33.6⫾1.1 years). The reference group
(controls) consisted of 33 normally active males. Control subjects
were not engaged in structured sporting activity and performed ⱕ3
30-minute bouts of moderate exercise per week. The age of control
subjects was 24 to 44 years old (mean age: 30.8⫾1.0 years; P⬎0.05
versus athletes). Athletes were tested during the “off season” period,
ie, at ⱖ 2 months after or before competition. The amount of exercise
during this period is relatively low, aiming to sustain rather than
increase physical fitness. Neither athletes nor controls had exercised
for at least 24 hours before the tests. None of the subjects was using
any lipid-lowering medication, performance-enhancing drugs or
food additives, drank alcohol excessively, or smoked. Subjects fasted
for 12 hours before blood collection.
The study was approved by the Alfred Hospital Ethics Committee
and conducted in accordance with the Declaration of Helsinki of the
World Medical Association.
Received December 14, 2003; revision accepted March 24, 2004.
From Baker Heart Research Institute (Wynn Domain) (B.O., B.A.K., A.H., L.S., P.N., D.S.), Melbourne, Victoria, Australia; and Daiichi Pure
Chemicals (O.M.), Tokyo, Japan.
Correspondence to Dr Dmitri Sviridov, Baker Heart Research Institute, Commercial Rd, PO Box 6492 St. Kilda Rd. Central, Melbourne, Victoria,
8008, Australia. E-mail [email protected]
© 2004 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
1087
DOI: 10.1161/01.ATV.0000128124.72935.0f
1088
Arterioscler Thromb Vasc Biol.
June 2004
Peak Pulmonary Oxygen Uptake
Peak pulmonary oxygen uptake (VO2max: a measure of aerobic
fitness) was determined during continuous incremental upright
cycling to volitional exhaustion on an electronically braked ergometer. Expired air was analyzed for volume, O2 and CO2 using
calibrated analyzers.9
Blood Collection
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After providing written informed consent the participants attended
the Alfred Hospital at 9:00 AM. Blood (20 mL) was collected by a
venepuncture into tubes containing streptokinase (Sigma; final concentration 150 U/mL) as the only anticoagulant. Blood was immediately cooled and plasma was isolated by centrifugation for 15
minutes at 4°C. Plasma was then aliquoted, snap-frozen in liquid
nitrogen, and kept at ⫺80°C. Aliquots were used once and not
refrozen. It was demonstrated in preliminary experiments that under
these conditions, the concentration of pre␤1-HDL remains the same as in
fresh samples and does not change for at least 1 year. These strict
conditions were essential because keeping plasma at ⫹4°C for ⬎3
hours, as well as prolonged storage at ⫺20°C, slow freezing, or repeated
freezing and thawing of plasma lead to elevation of pre␤1-HDL levels,
probably because of decay of mature HDL particles.10
Lipids, Lipoproteins, Cholesteryl Ester Transfer
Protein, and Lecithin:Cholesterol Acyltransferase
Plasma total cholesterol (TC), triglyceride (TG), LDL cholesterol,
apolipoprotein B (apoB), HDL cholesterol, and apolipoprotein A-I
(apoA-I) were measured using spectrophotometric techniques with a
Cobas-FARA centrifugal analyzer (Roche Diagnostic Systems).
Pre␤1-HDL concentration was measured by enzyme-linked immunosorbent assay (ELISA)11 (Daiichi Pure Chemicals, Tokyo, Japan).
Standard samples were included in each round of determinations to
account for the effect of interexperimental variations. The coefficient
of variation for pre␤1-HDL assay was 8%. Changes in concentration
of pre␤1-HDL determined by ELISA correlated with changes determined by 2-dimensional nondenaturing electrophoresis.10
Cholesteryl ester transfer protein (CETP) and lecithin:cholesterol
acyltransferase (LCAT) concentrations were measured by ELISA
(Daiichi). CETP activity was measured by fluorometric assay (Roar
Biomedical, New York, NY). LCAT activity was measured by the
method of Bielicki et al.12
Cholesterol Efflux
Plasma cholesterol efflux was measured in 19 athletes and 24
controls (randomly selected). RAW-264.7 mouse macrophage cells
were labeled by incubation with serum-containing medium containing [3H]cholesterol (Amersham; specific radioactivity 1.8 TBq/
mmol; final radioactivity 75 kBq/mL) for 48 hours at 37°C. Cells
were then washed 3 times with phosphate-buffered saline and
incubated for 18 hours in serum-free medium containing 0.1%
bovine serum albumin (essentially fatty–acid-free; Sigma). After the
second incubation, cells were again washed and incubated for 2
hours with serum-free medium containing 2% plasma from subjects.
Media and cells were then collected and radioactivity determined on
a ␤-counter. Cholesterol efflux was defined as the amount of
radioactivity in the medium divided by the amounts of radioactivity
in the medium and cells ⫻100%. To account for interexperimental
variations, a standard sample of plasma was included in each
experiment.
Figure 1. Dependence of plasma concentrations of HDL cholesterol (A) and apoA-I (B) on the level of aerobic fitness. HDL cholesterol and apoA-I concentrations were determined using
COBAS plasma analyzer as described in Methods section. F
indicates controls; Œ, athletes.
Results
Physical Parameters and Non-HDL Lipids
The 2 groups investigated in this study were endurancetrained athletes and a normally active reference group (controls). Blood samples were taken at least 24 hours after
exercise to exclude the effect of acute exercise. Choosing a
normally active comparison group avoided a number of
possible confounding factors, such as hypertriglyceridemia,
obesity, and metabolic syndrome associated with sedentary
lifestyle. The groups were well matched by age, body mass
index (BMI) and waist-to-hip ratio (Table). There was no
significant correlation between age, BMI, or waist-to-hip
ratio and any lipid parameter. There was also no statistically
significant difference between the 2 groups in plasma content
of TC, TG, LDL cholesterol, and apoB (Table). Aerobic
fitness measured as VO2max was significantly higher in
athletes (P⬍0.001) (Table).
HDL
Plasma concentrations of HDL cholesterol and apoA-I were
higher in athletes compared with controls. On average, HDL
Parameters of Lipid Metabolism in Athletes and Normally
Active Group (Controls)
Parameter
Controls
Athletes
P
VO2max (mL/min per kg)
38.8⫾1.0
53.4⫾1.2
⬍0.001
BMI (kg/m2)
23.2⫾0.4
23.9⫾0.5
NS
Waist/hip ratio
1.00⫾0.01
0.98⫾0.01
NS
TC (mmol/L)
4.9⫾0.1
5.2⫾0.2
NS
LDL-C (mmol/L)
2.9⫾0.2
3.2⫾0.2
NS
apoB (mg/dL)
73.4⫾3.0
75.9⫾3.5
NS
TG (mmol/L)
1.1⫾0.1
0.9⫾0.1
NS
HDL-C (mmol/L)
1.4⫾0.1
1.7⫾0.1
⬍0.001
apoA-I (mg/dL)
128⫾3
145⫾2
⬍0.001
Pre␤1-HDL
37⫾3
54⫾4
⬍0.001
LCAT mass (␮g/mL)
7.0⫾0.3
6.6⫾0.4
NS
Statistics
LCAT activity (nmol/␮l per h)
24.2⫾1.4
29.8⫾1.2
⬍0.005
All results are expressed as means⫾SEM. Group characteristics
were compared by 1-way ANOVA. Correlations were calculated as
Pearson product–moment correlation. In Figure 1, deviation from a
linear relationship was defined by a breakpoint. The breakpoint was
determined be arranging VO2max values in ascending order, and
including sequential values in the regression until inclusion of
additional values caused a reduction in the Pearson correlation
coefficient. The breakpoint was thus defined as the highest VO2max
value included in the linear regression.
CETP mass (␮g/mL)
1.7⫾0.1
2.0⫾0.1
NS
CETP activity (nmol/mL per h)
73⫾2
67⫾3
NS
Cholesterol efflux (%)
16.2⫾0.3
18.8⫾0.8
⬍0.02
Cholesterol efflux per apoA-I unit
0.13⫾0.01
0.13⫾0.01
NS
Mean⫾SEM is shown.
N⫽ 25 athletes and 33 controls, except for cholesterol efflux studies when
n⫽19 athletes and 24 controls.
Olchawa et al
Physical Fitness and RCT
1089
Figure 4. Dependence of cholesterol efflux on plasma concentrations of HDL cholesterol (A) and apoA-I (B). Cholesterol efflux
was determined as the capacity of plasma (final concentration
2%) to promote cholesterol efflux from RAW cells labeled with
[3H]cholesterol during 2-hour incubation. Cholesterol efflux was
defined as the amount of labeled cholesterol in the medium
divided to the amount of labeled cholesterol in the medium and
cells ⫻100%. Details of the experiment are described in Methods section. F indicate controls; Œ, athletes.
Downloaded from http://atvb.ahajournals.org/ by guest on June 14, 2017
Figure 2. Dependence of plasma concentration of pre␤1-HDL on
the level of aerobic fitness. Pre␤1-HDL concentration was determined by sandwich ELISA as described in Methods section. F
indicates controls; Œ, athletes.
cholesterol was 21% higher and apoA-I was 13% higher in
athletes (Table). HDL cholesterol concentration correlated
positively and significantly (r⫽0.6; P⬍0.001) with aerobic
fitness at lower values of VO2max, but linear dependence
ceased to be significant when higher VO2max values were
included (Figure 1A). The breakpoint of the linear relationship was determined to be 51 mL/min per kg. Above this
point, there was no statistically significant correlation between HDL cholesterol and VO2max. A similar relationship
was observed between aerobic fitness and plasma concentrations of apoA-I (r⫽0.6; P⬍0.001) (Figure 1B).
Mean concentration of pre␤1-HDL was 46% higher in
athletes compared with control subjects (Table). Plasma
concentration of pre␤1-HDL correlated with VO2max (r⫽0.4;
P⬍0.01) (Figure 2) and with plasma levels of HDL cholesterol (r⫽0.4 P⬍0.01) and apoA-I (r⫽0.4; P⬍0.002) (Figure
3A and 3B).
LCAT
The concentration of LCAT was similar for athletes and
control subjects; however, the activity of LCAT was 23%
higher in athletes (P⬍0.005) (Table). There was no correlation between LCAT activity or mass and HDL cholesterol,
apoA-I, and pre␤1-HDL concentrations in the plasma. There
was also no correlation between LCAT mass and activity.
Figure 3. Dependence of plasma concentration of pre␤1-HDL on
concentrations of HDL cholesterol (A) and apoA-I (B). Pre␤1-HDL
concentration was determined by sandwich ELISA as described
in Methods section. HDL cholesterol and apoA-I concentrations
were determined using COBAS plasma analyzer as described in
Methods section. F indicates controls; Œ, athletes.
CETP
There was no difference between athletes and controls in
either CETP plasma content or CETP activity (Table). There
was also no correlation between CETP mass or activity and
HDL cholesterol, apoA-I, pre␤1-HDL, TG, LCAT activity, or
mass.
Cholesterol Efflux
Cholesterol efflux was tested as the capacity of plasma to
promote cholesterol efflux from a macrophage cell line. Mean
cholesterol efflux to plasma samples from athletes was 16%
higher compared with that from controls (P⬍0.03) (Table).
However, when cholesterol efflux was related to the concentration of apoA-I (which reflects the number of HDL particles), the difference between the 2 groups was eliminated
(Table). We conclude that enhanced cholesterol efflux to
plasmas from athletes was caused by a greater number of
HDL particles, rather than to an increased ability of HDL
particles to promote cholesterol efflux. Accordingly, there
were significant positive correlations between cholesterol
efflux and HDL cholesterol and apoA-I concentrations in
plasma (r⫽0.4; P⬍0.02 for HDL cholesterol and r⫽0.3;
P⬍0.05 for apoA-I) (Figure 4A and 4B).
Cholesterol efflux did not correlate with pre␤1-HDL concentration or with LCAT or CETP mass or activity.
Discussion
The effect of physical exercise on plasma HDL levels has
been demonstrated in a number of intervention studies.
Long-term,3 short-term,13 and even single-session14 exercise
all increase HDL cholesterol levels. A similar effect was
found in several cross-sectional studies.5 The present study
was aimed at: (1) investigating potential mechanisms mediating the effect of exercise on HDL levels; and (2) determining whether exercise induced increases in HDL cholesterol
reflects increased functionality of RCT.
The major finding of this study was that physical fitness
was associated with increments in plasma concentrations of
HDL cholesterol, apoA-I, pre␤1-HDL, activity of LCAT in
plasma, and in the capacity of plasma to promote cholesterol
efflux from macrophages.
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Higher levels of HDL cholesterol and apoA-I in physically
fit people was an expected finding and the magnitude was
consistent with other cross-sectional5 and intervention studies.3,13 Dependence of HDL cholesterol and apoA-I on the
level of aerobic fitness was linear up to a value of VO2max of
51 mL/min per kg; however, further increases in fitness were
not accompanied by a further increase in HDL levels (Figure
1). Previous studies have also observed a low threshold in
relation to the amount of exercise required to initiate an
increase in HDL.5 Such a threshold was not observed in the
current study, which is likely because of our normally active
rather than sedentary control group. The presence of an upper
threshold is a new finding, because the effect on HDL
cholesterol was thought to be proportional to physical activity
even at higher levels of fitness.3 This finding, however, is
consistent with conclusions of Durstine et al,15 who found a
significant difference in HDL cholesterol between “recreational” and “good” runners, but not between “good” and
“elite” runners. The reasons for the existence of an upper
threshold are not clear. We speculate that it might be related to
the threshold in the increase of muscle mass associated with
increasing fitness or factors linked to the catabolism of HDL.
Another novel finding of this study was that higher levels
of fitness were accompanied by higher concentrations of
plasma pre␤1-HDL. This finding is consistent with previously
reported increases in pre␤1-HDL after exercise.16,17 We have
previously demonstrated that pre␤1-HDL is generated during
passage of blood from artery to vein across human leg
muscles and that this can be substantially stimulated by
exercise.16 Because athletes have a bigger muscle volume, we
speculate that muscle may be an important source of higher
pre␤1-HDL levels in athletes.
Pre␤1-HDL is considered to be the first product of lipidation of minimally lipidated apoA-I and a likely acceptor of
cellular cholesterol.7,18,19 Plasma levels of pre␤1-HDL are
higher in patients with hypercholesterolemia,11 CAD,20 and
obesity.21 Because the magnitude of changes in pre␤1-HDL
concentration usually exceed that in HDL cholesterol, and
because pre␤1-HDL levels rapidly respond to treatment (eg,
weight loss22), it has been suggested that pre␤1-HDL may be
a better marker of RCT than HDL cholesterol.7 We have
previously suggested that pre␤1-HDL might be a marker of
formation of HDL from minimally lipidated apoA-I (both
synthesized de novo and recycled during HDL remodeling)
and cellular cholesterol, a rate-limiting step in RCT.19 Consistent with our previous results,23 there was no correlation
between pre␤1-HDL concentration and the capacity of plasma
to promote cholesterol efflux, suggesting that pre␤1-HDL is
more likely to be a product rather than an initiator of the
efflux. Higher levels of pre␤1-HDL in dyslipidemia might
therefore reflect higher activity of RCT in response to
accumulation of cellular cholesterol caused by higher levels
of plasma cholesterol or result from increased remodeling of
triglyceride-enriched HDL by hepatic lipase in obese and
dyslipidemic patients. It is, however, premature to draw
conclusions regarding the relationship between pre␤1-HDL
concentration and atherosclerosis. Asztalos et al reported
either no difference in pre␤1-HDL between men with or
without CAD24 or a higher pre␤1-HDL/␣1-HDL ratio in
subjects with more severe coronary artery stenosis.25 Miida et
al have reported higher pre␤1-HDL values among Japanese
men with CAD.20 The mechanisms responsible for such
differences between patients with CAD and healthy subjects
have not been studied and may be multiple. The concentration
of pre␤1-HDL in plasma is a reflection of the rate of its
formation (result of cholesterol efflux and lipolysis of triglyceride-rich lipoproteins) and remodeling (through the action of
LCAT).7 Thus, the level of pre␤1-HDL could reflect the sum
of both these steps and should be interpreted in a context of
changes in other parameters of RCT.
It is important to recognize that anti-pre␤1-HDL antibody
used in the assay reacts with epitopes of apoA-I masked
during apoA-I lipidation but exposed on pre␤1-HDL and
lipid-free apoA-I.19 However, when human plasma or delipidated apoA-I were separated on 2-dimensional nondenaturing
electrophoresis, no fraction corresponding to lipid-free
apoA-I was found in plasma. When plasma was pretreated
with the anti pre␤1-HDL antibody the pre␤1-HDL fraction
was the only fraction that had shifted, no other fraction being
affected by the antibody.11 This evidence indicates that there
are no detectable amounts of fully delipidated apoA-I in
human plasma.
The capacity of plasma from athletes to promote cholesterol efflux was enhanced compared with controls, but the
increased number of HDL particles fully accounted for this
effect. This indicates that athletes are capable of producing
more HDL particles, but the ability of these HDL particles to
promote cholesterol efflux is unchanged.
Contributing to the higher HDL cholesterol in the athletes
was their higher LCAT activity, an observation consistent
with that of Lehmann et al26 and Gupta et al.27 It may be
speculated that the increase in LCAT activity without an
increase in LCAT mass is secondary to the higher concentration of its major substrate and possible carrier, pre␤HDL,28 which is consistent with the fact that we found no
correlation between plasma mass and activity of LCAT
despite at least 2- to 3-fold variation in each of the parameters. It has been demonstrated by Chung et al29 that activity of
LCAT depends on its distribution among different lipoproteins, with LCAT residing on lipoproteins other than HDL3
being only minimally active. Possibly, lack of correlation
between LCAT mass and activity reflects distribution of
LCAT between lipoprotein subfractions.
Recent studies on the process of RCT suggest that it is
likely to be comprised of the following steps:7 (1) efflux of
cellular cholesterol on lipid-free or minimally lipidated
apoA-I. The process is most likely modulated by ABCA1 and
results in formation of pre␤1-HDL particles; (2) further efflux
of cholesterol to pre␤1-HDL with the formation of larger
discoid HDL particles; (3) esterification of cholesterol with
LCAT resulting in formation of spherical HDL; (4) maturation of HDL: formation of large HDL particles either by
acquiring and esterifying additional cholesterol from other
lipoproteins or by fusion of smaller HDL particles; and (5)
remodeling of mature HDL by the action of CETP, phospholipid transfer protein (PLTP), hepatic lipase, and scavenger
receptor type B1 (SR-B1) with the formation of smaller HDL
particles and minimally lipidated apoA-I. The latter may
Olchawa et al
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undergo further lipidation with cellular cholesterol. Higher
levels of HDL cholesterol, which mainly represent mature
HDL particles, may be caused by increased formation of
these particles (“anabolic” arm of RCT, stages 1 to 4) or
caused by retarded remodeling of mature HDL (“catabolic”
part, stage 5). The former situation would likely indicate
increased functionality of RCT, whereas the latter would be
indicative of a dysfunctional RCT.7
Summarizing our findings, we established that a high level
of fitness is accompanied by enhanced capacity of plasma to
promote cholesterol efflux (step 1 of RCT), increased concentration of pre␤1-HDL (steps 1 and 2), increased activity of
LCAT (step 3), and higher concentration of HDL cholesterol
(step 4). All these steps represent the anabolic arm of RCT
and are involved in formation of mature HDL. However, at
least 1 key parameter of the catabolic arm of RCT, CETP,
was unchanged. We hypothesize that higher levels of HDL
cholesterol in athletes may be a consequence of increased
formation of HDL from apoA-I and cellular cholesterol,
enhanced flow of cholesterol along the RCT pathway, and
hence increased functionality of RCT. Similar changes in
RCT were observed when formation of HDL was induced by
intravenous infusion of apoA-I/phospholipid discs in humans30 or oral administration of dimyristoylphosphocholine
to apoE⫺/⫺ mice.31 The latter was accompanied by marked
reduction of atherosclerosis.
Acknowledgments
This work was supported by the National Health and Medical
Research Council of Australia and by a research grant from Daiichi
Pure Chemicals, Tokyo.
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Downloaded from http://atvb.ahajournals.org/ by guest on June 14, 2017
Physical Fitness and Reverse Cholesterol Transport
Beata Olchawa, Bronwyn A. Kingwell, Anh Hoang, Laurence Schneider, Osamu Miyazaki, Paul
Nestel and Dmitri Sviridov
Arterioscler Thromb Vasc Biol. 2004;24:1087-1091; originally published online April 8, 2004;
doi: 10.1161/01.ATV.0000128124.72935.0f
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