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 However, when Met Synd individuals were withdrawn from statins for 4 days and their basal blood TG concentration increased, exercise neither reduce PPTG (i.e., EXER+PLAC vs REST+PLAC; Figure 1).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).