In this study we evaluated the effect of obesity on plasma lipoprotein concentrations and the lipoprotein subclass distribution. We studied men and women who were free of clinically significant alterations in substrate metabolism to avoid potential confounding due to marked dyslipidemia and insulin resistance, which are often present in obese individuals.7
We found that obesity, even in the absence of clinically significant imbalances in glucose and lipid homeostasis, was associated with a 50% to 100% increase in the concentrations of the pro-atherogenic lipoproteins VLDL, IDL, and LDL, as well as a small, and biologically probably insignificant, increase (by ~10%) in HDL particle concentration. Furthermore, we found that obesity was associated with a shift towards a pro-atherogenic subclass distribution, the most marked of which was the change towards predominately small LDL; in addition, there was a shift, although less marked, towards small HDL and an even less pronounced shift towards large VLDL. These changes in lipoprotein profile likely increase CHD risk3–5
in obese subjects who are considered healthy on the basis of their blood biochemistries and plasma glucose and lipid concentrations. On the other hand, the female CHD risk advantage is probably largely related to differences in traditional lipid risk factors (e.g., plasma TG and HDL-cholesterol concentrations) because there were no sex differences in the concentrations of circulating IDL, LDL (total and subclasses) and HDL (total) particles and the differences between men and women in VLDL (total and large) particle concentration and HDL subclass profile, although statistically significant, were relatively minor.
Our findings regarding the effect of obesity on plasma lipoprotein subclass concentrations confirm and extend the observations made earlier by other investigators. In agreement with our results, obesity is almost uniformly reported to be associated with increased total plasma apolipoprotein (apo) B-100 concentration due to increased concentrations of all three apoB-100 containing lipoprotein classes (i.e., VLDL, IDL and LDL).37
In addition, obesity has previously been found to be associated with increased concentrations of small, dense LDL particles and smaller average LDL particle size9,10,15,18,20,25
as well as smaller average HDL particle size due to reciprocal changes in the concentrations of small (increased) and large (decreased) HDL particles.16,18,19,38
However, in all of these earlier studies it was not clear whether these changes were largely the result of obesity (as in our study) or due to obesity-related metabolic comorbidities, because most studies included individuals with clinically significant dyslipidemia (e.g., fasting plasma TG concentrations as high as 200–400 mg/dl)9–11,15,16,18–20
and fasting hyperglycemia (plasma glucose concentrations as high as 110–130 mg/dl),9,11,15,18
while others included individuals with variable drinking and smoking habits and subjects who used medications.20,25,38
Existing data regarding the effect of obesity on VLDL subclass distribution is inconclusive. By using cumulative flotation ultracentrifugation, Bioletto et al
observed no differences in the concentrations of three VLDL subfractions in lean and obese subjects (both men and women). However, by using NMR spectroscopy, MacLean et al
found no differences in VLDL subclass concentrations and average VLDL size between some lean and obese subject groups but not others and other investigators, also relying on NMR spectroscopy measurements, reported positive associations between adiposity measures and average VLDL particle size14,21
and particularly with large VLDL subfraction concentrations.13,18,21
The discrepancy in results is probably due to differences in the metabolic characteristics of subjects because fasting glucose, insulin and TG concentrations, glucose intolerance, and insulin resistance have all been shown to influence the distribution and size of VLDL.13,14,21–24
In fact, the strength of the relationship between these metabolic parameters and VLDL subclass profile is stronger than that for LDL and HDL,14,21,23,39
indicating that VLDL subclass distribution and size might be particularly susceptible to these influences.
The pro-atherogenic effect of obesity on the plasma lipoprotein profile was present in both sexes and was of similar magnitude in men and women. However, independent of obesity, we discovered differences between the sexes in the concentration of VLDL particles (all subclasses), which was reduced in women, and the subclass distribution of HDL, which was shifted towards larger particles at the expense of smaller ones in women. The concentrations of IDL, LDL (all subclasses) and total HDL particles were not different between the sexes. As is the case with the traditional CHD risk factors (e.g., plasma TG and HDL-cholesterol concentrations), differences between sexes in the lipoprotein subclass profile are not due to differences in body composition between men and women because women have more body fat than men and yet a less pro-atherogenic plasma lipoprotein profile. In addition, the observed sex differences were small and it remains unclear whether they significantly contribute to the reduced CHD risk in women, beyond the differences in traditional lipid risk factors. For instance, women typically have 20–40% lower plasma TG and higher HDL-cholesterol concentrations than men,22,27,40–43
whereas sex differences in VLDL particle concentrations and HDL subclass distribution profile in our study were generally around 10% or less.
The differences in HDL subclass distribution between our men and women are in agreement with previous population-based studies using NMR spectroscopy, in which total HDL particle number was found to be the same in men and women but the HDL subfraction distribution was shifted towards larger particles and average HDL size was greater in women than in men.22,26,27,44
In addition, our finding regarding lower VLDL particle concentrations in women than in men is in agreement with previous reports.22,26,27
However, we and other small cohort studies26
found no difference between the sexes in VLDL particle size, whereas population-based studies reported smaller average VLDL size in women than in men, the difference being around 7–8%.22,27,28
Our inability to detect a statistically significant difference of smaller magnitude (2–6% in our subjects) is therefore likely due to the relatively small sample size. Part of the discrepancy in outcomes between studies may also rest on differences in subject characteristics, such as subjects’ BMI, plasma TG and HDL-cholesterol and insulin concentrations, which have been shown to influence the magnitude of sex differences in VLDL particle size.22,39,44
In contrast to the results from our study, in which there is no indication for sex differences in either total LDL particle concentration or subclass distribution and average particle size, LDL subclass profile was shifted towards larger particles and LDL size was greater in women than in men in all19,20,22,26,27,29,45–54
reports on this issue that we are aware of. However, the reported sex differences in LDL particle size are typically in the range of 1–2%19,20,22,26,27,29,48–50,52
and may therefore only be detected in much larger samples than ours.22,50,52
Moreover, most of these studies included lean, overweight, and obese individuals combined, with plasma TG concentrations as high as 200–400 mg/dl,19,20,22,26,27,29,48–50,52
which complicates the interpretation of these earlier reports. Indeed, studies that stratified their cohort according to plasma TG concentration found that the sex difference in LDL particle size was only present in subjects with hypertriglyceridema (plasma TG concentration > 200 mg/dl)48
but not among normotriglyceridemic men and women (plasma TG concentration < 150 mg/dl).48,55
Our men and women were matched for BMI and insulin resistance (as indicated by the HOMA-IR) within the lean and obese groups, and plasma TG concentrations in both lean and obese men and women were within the normal range (< 150 mg/dl). Thus, we conclude that when men and women are healthy and well-matched, there is no sex difference in LDL size or subclass distribution.
The mechanisms underlying the observed effects of obesity and sex on plasma lipoprotein concentrations and subclass distribution are not well understood. Obesity is characterized by hepatic overproduction of VLDL-apoB-100 (i.e., VLDL particles), decreased catabolism of apoB-100 containing lipoprotein particles (VLDL, IDL, and LDL) and increased turnover of apoA-I containing HDL particles,37,56
which is consistent with higher VLDL, IDL, and LDL particle concentrations and a shift towards smaller HDL particles in obese compared with lean subjects. The size of circulating apoB-100 containing lipoprotein particles is largely determined by their TG content, and studies examining the effect of obesity on VLDL-TG kinetics reported an increase in VLDL-TG secretion in obese men and impaired plasma VLDL-TG clearance in obese women,31
which may underlie the larger circulating VLDL particles in obese than lean subjects. The alterations in the relevant mechanisms determining IDL and LDL particle sizes in obesity are not clear, but they are related to the metabolism of their precursor, i.e., VLDL (both VLDL-TG and VLDL-apoB-100), as well as the catabolism of the IDL/LDL-TG and IDL/LDL-apoB-100.57–59
Sex differences in VLDL-apoB-100 (i.e., VLDL particle) metabolism are small and have been examined mainly among lean, overweight and obese individuals combined;60
still, lean women secrete fewer VLDL particles (i.e., VLDL-apoB-100) than lean men61
consistent with their lower total VLDL particle concentration. Similarly, there is no difference between normotriglyceridemic (plasma TG concentration < 185 mg/dl) men and women in IDL-apoB-100 and LDL-apoB-100 kinetics,62,63
consistent with the absence of sex differences in IDL and LDL subfraction concentrations and LDL subclass distribution and particle size. Studies evaluating HDL-apoA-I and apoA-II kinetics generally report some64–66
differences between men and women, indicating relatively small effects on HDL metabolism. Clearly, more kinetic studies are needed to better understand the mechanisms responsible for the observed effects of obesity and sex on plasma lipoprotein profile.
In summary, we found that obesity is not only associated with a significant increase in circulating pro-atherogenic lipoprotein particles (i.e., VLDL, IDL, LDL) but also leads to unfavorable, pro-atherogenic alterations in VLDL, LDL, and HDL subclass distributions, namely a disproportionate increase in the concentration of large VLDL and small LDL, and an increase in the concentration of small HDL at the expense of large HDL. Importantly, the effect of obesity on the lipoprotein subclass profile is evident in the absence of clinically significant imbalances in plasma glucose and lipid homeostasis, and is qualitatively the same in men and women, although women have overall fewer circulating VLDL (all subclasses) and fewer small but more large HDL. These alterations in obese subjects likely increase their risk for CHD3–5
even in the absence of clinically manifest dyslipidemia and hyperglycemia; the female CHD risk advantage is largely related to the traditional lipid risk factors (e.g., plasma TG and HDL-cholesterol concentrations) because the differences between men and women in lipoprotein particle concentration and subclass profile are comparably minor.