DISCUSSION
The main finding of this study is that whilst a bout of aerobic exercise
reduced by 46% the area of postprandial TG vs time curve in
normolipidaemic metabolically healthy (Met Health) individuals, the same
session of exercise (same relative intensity and duration) had no effect
on PPTG in metabolic syndrome (Met Synd) hypercholesteraemic
individuals. Since these individuals were medicated to treat their
hypercholesterolemia with statins, we presumed that statin strong effect
on lowering PPTG (i.e., 35% in average, Figure 1) did not permit to
appreciate the effects of exercise on lowering PPTG. However, when Met
Synd individuals were withdrawn from statins for 4 days and their basal
blood TG concentration increased, exercise neither reduce PPTG (i.e.,
EXER+PLAC vs REST+PLAC; Figure 1). Our data suggest that Met Synd had a
limitation (i.e., resistance) to respond to exercise with reductions in
PPTG in comparison to metabolically healthy counterparts.
Some reports show that individuals with obesity and Met Synd have a PPTG
lowering response to exercise [16,
17]. However, those studies did not
directly compare the responses of Met Synd to a Met Healthy group. When
lean individuals are compared to age-matched obese counterparts exercise
causes similar PPTG reductions in both groups
[18,
19]. The obese individuals in these
studies were young (15-48 years) with blood lipid levels (i.e., total
cholesterol and LDL-c) in the same range than the lean group. In
contrast, our sample is composed of obese (BMI=30±4
kg·m-2) older (61±7 years old; Table 1) individuals
that have been diagnosed and treated against hypercholesterolemia with
statins for 5 years in average. In our Met Synd individuals with chronic
disarrangements in their lipid metabolism we do not observe an effect of
exercise alleviating PPTG. Our results are not isolated since others
have reported that moderately intense and prolonged (i.e., 60 min) of
exercise did not lower PPTG response in Met Synd individuals
[20]. Likewise, in diabetic type 2
individuals, a bout of 40-90 min of moderately intense exercise (40-60%
VO2max) neither lowers PPTG
[21,
22]. Our data suggest that older obese
individuals with excess blood lipid levels to the point of needing
pharmacological treatment, are more prone to be resistant to the effects
of a bout of exercise on lowering PPTG.
Although exercise did not have an effect on postprandial lipoproteins in
Met Synd individuals, their habitual statin medication was very
effective at reducing PPTG and other lipids (Figure 2). Of note, statin
in Met Synd normalize the concentrations of total cholesterol and LDL-c
to levels that were not different that in the Met Healthy group (Table
2). However, statin did not reduce TG or VLDL-c to the levels of Met
Healthy (Table 2). Statin had a reductive effect on Apo B48
concentration (Figure 3) a fair surrogate of chylomicron metabolism.
Reductions in the postprandial initial rise of the Apo B48 concentration
curve would suggests reduction in chylomicron secretion with statins.
Other studies have not observed a reduction in the initial slope
[8, 23]
arguing that statins increase chylomicron clearance
[24]. It is uncertain from our data
(Figure 3) if statins blunt the initial rise in Apo B48 after the meal.
More frequent sampling during the first 2 hours after the meal is
required to explore this possibility.
Several studies have examined the kinetics of Apo B48 by infusing a
bolus of isotopically labeled leucine to measure the incorporation of
this amino acid into Apo B48. One recent study on healthy normolipemic
men reveals that atorvastatin (80 mg·day-1) reduces
both the number of Apo B48 particles secreted in response to the fat
load (-29%; P<0.01) while at the same time increasing Apo B48
fractional catabolic rate (i.e., FCR; +32%, P<0.001;
[25]). In another study, atorvastatin
(20 mg·day-1) in adults with combined hyperlipidemia,
reduces postprandial Apo B48 production rate (-16%; P=0.104; NS) and
increases FCR (11%; P=0.102; NS) while a higher dose (i.e., 80
mg·day-1) has a larger effect on FCR than in
production rate [26]. Thus, current
literature does not discard an effect of statins on reducing
postprandial production of chylomicrons although it favors increased
clearance.
The putative mechanism by which statin reduce PPTG is that the
statin-induced increased LDL receptor activity may enhance the removal
not only of LDL-c but also of triglyceride-rich lipoprotein and
chylomicron remnants. However, apolipoprotein B48 (marker of chylomicron
concentration) does not bind to LDL receptor and requires the Apo E
moiety for hepatic removal of chylomicrons. In turn, Apo E activity is
inhibited by C apolipoproteins. It has been documented that statins
reduce Apo C-III [9] liberating the
inhibition of Apo C-III on lipoprotein lipase (LPL). Some studies
support that atorvastatin increase LPL activity
[27] which may explain the reduction
observed in PPTG in the present data with statin use (Figure 1).
Parhofer et al., [8] found that in
hypertriglyceridemic individuals, atorvastatin reduced large
triglyceride rich lipoproteins (i.e., TRL composed of chylomicrons and
VLDL) but not small TRL (i.e., their remnants). They argue that the
increased conversion of chylomicrons to chylomicron remnants balances
the increased turnover of chylomicron remnants observed in
hypertriglyceridemic individuals. A similar mechanism may be explaining
our reduction in Apo B48 with statins in hypercholesterolemic Met Synd
individuals while unchanged Apo B100 (Figure 3). Statins may induce to
complete chylomicron catabolism with unavoidable loss of Apo B48, but
only partial hydrolysis of the triglyceride content of large VLDL
converting them into VLDL remnants without the loss of Apo B100 in their
lipoprotein core. In our study, plasma triglycerides decreased from a
mean of 865±495 to 557±304 mg·dL-1 which meant a 35%
reduction in iAUC of TG (Figure 1). Since Apo B100 did not change with
statins, the ratio of triglyceride to Apo B100 was significantly
reduced. This suggests that statins may have a beneficial effect by
producing a triglyceride poor postprandial lipoprotein particle in
individuals with Met Synd. A decrease in this ratio might also decrease
the risk of coronary artery disease
[28]. Finally, our data argue against
the linear association between Apo B liver secretion and triglyceride
concentration that others have proposed
[29].
This study has several limitations. Our two groups of subjects were not
matched by fitness, body composition or age. However, we sought to study
if pharmacological (statin) or non-pharmacological (exercise) therapies
could return postprandial lipoprotein response to normality and thus, we
recruited a group of undoubtedly metabolically healthy individuals
(although younger and leaner) from the same population. Secondly, Met
Synd subjects were taking different types and dosages of statins with
different pharmacokinetics. However, to ensure a full wash out effect,
statins were withdrawn during 96 hours which is 5 times the half-life
time of the more resilient statin (rosuvastatin). One of the strengths
of this study, is that normally, lipoproteins are separated by
ultracentrifugation based on density gradients. However, this method
does not separate lipoprotein fractions containing chylomicrons and
chylomicron remnants but rather heterogenous particle populations
containing both Apo B100 and Apo B48. Thus, it is not rare that the
chylomicron fraction (large TRL) contains more hepatically derived (Apo
B100) than intestinally derived particles
[8]. In this study we have directly
analyzed in plasma Apo B48 and B100 using enzyme-linked immunosorbent
assay (ELISA) which has high sensitivity and specificity for these
proteins and thus we are confident on our surrogate indexes of
intestinal and hepatic lipoprotein concentration.
In summary, our data suggest, that a bout of aerobic exercise is not
effective on reducing PPTG in hypercholesterolemic Met Synd individuals.
The actions of exercise were neither evident when statins were withdrawn
to better study the possible effects of exercise. Finally, the same
exercise bout lowered PPTG in metabolically healthy individuals. These
three results combined, suggest that hypercholesterolemic Met Synd
individuals are “resistant” to the beneficial effects of exercise on
lowering PPTG. However, statins were very effective lowering fasting and
PPTG in hypercolesterolemic Met Synd individuals throughout an increased
metabolism of the intestinally derived chylomicrons (i.e., Apo B48).