The present study focused on the PPL response to an acute (1-time) high-fat meal using data derived from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. We sought to describe lipoprotein particle subclass number, size, and concentrations stratified by gender and baseline triglyceride status. Although the pattern of change observed for both men and women was qualitatively similar, the magnitude of these changes appeared to be more exaggerated in men compared to women, especially for VLDL and TG response. Similar to the response demonstrated by gender, the pattern of change was qualitatively similar for normo- and hyper-triglyceridemic individuals; however, the magnitude was more exaggerated among hyper-triglyceridemic than normo-triglyceridemic individuals.
Specifically, in terms of lipoprotein particles for both normo- or hyper-triglyceridemic individuals, we observed little change in total particle number over the 3 time points (up to 6 hours after the meal) for either total LDL or HDL particle number. In contrast, for normo-triglyceridemic subjects, total VLDL particle number appeared to rise above baseline at 3.5 hours and drop considerably below baseline at 6 hours after the high-fat meal. This pattern was considerably different in hyper-triglyceridemic individuals where, in both men and women, we observed a precipitous drop relative to baseline which continued from the 3.5 to the 6 hour time point.
Despite expected baseline differences between normo- and hyper-triglyceridemic individuals, there was a reduction in small LDL particle concentrations secondary to the PPL challenge. In normo-triglyceridemic individuals there was a persistent decline from baseline, while in hyper-triglyceridemic men and women small LDL particle concentration appeared to plateau.
The major pattern we observed among HDL particle subclasses was a significant shift to more medium HDL particles and fewer small HDL particles with a non-significant increase in HDL-C (p > 0.05 for men and women). Decewicz et al  observed decreases in medium HDL particles in a 73 case - 73 control study of a 1-year dietary lifestyle intervention; this contrasts to the observed increase in medium HDL observed among the 546 women and 502 men studied in the GOLDN cohort after an acute high-fat meal. It is likely that sample size and diet (Ornish diet low in fat  vs high fat (GOLDN)) are at the root of these differences in response. In a study examining the difference in particle distribution between diabetics and non-diabetics by Colhoun et al , diabetics had a lower concentration of small HDL and a larger concentration of large HDL and larger HDL sizes , a finding similar to ours; however, the Colhoun et al study was a descriptive study of fasting particle distributions and did not include a fat-loading intervention.
In our study, the total number of VLDL particles decreased during the postprandial period which was due to an increase in large VLDL and chylomicrons along with more substantial decreases in medium and small VLDL subclasses. A decrease in medium VLDL and total VLDL particles was also observed among the diabetic subjects in the study by Colhoun et al . Our study contained a small proportion of diabetics, thus rendering further stratification by diabetic status unfeasible. Furthermore, decreases in small/medium VLDL particles were demonstrated among women during the therapeutic lifestyle change diet by Li et al . The distributional shift in VLDL particle subclasses was consistent and somewhat expected since large VLDL and chylomicrons accept triglycerides in an effort to quickly repackage and remove them from the circulation ; however, the small reduction in total VLDL particles is unexpected, especially since VLDL-C increased in response to the acute high-fat meal.
During the PPL response to a high-fat meal, many changes occur during lipoprotein metabolism. It has been shown that HDL becomes enriched with TG, leading to increased removal of HDL from the plasma, thereby decreasing HDL-C . Also the transfer of cholesterol ester (CE), the main component of HDL, is increased due to the increased activity of cholesteryl ester transfer protein (CETP) during PPL , and CE is preferably transferred to chylomicrons , all of which are demonstrated in our study by a postprandial decrease in HDL-C and increase in chylomicrons. Similarly CE from LDL is also transferred to chylomicrons during PPL . Hepatic lipase (HL) activity also increases during PPL, thus catabolizing both HDL and LDL into smaller, denser HDL and LDL particles [17, 19]; however, increases in smaller, denser HDL and LDL were not clearly demonstrated in our population after a high-fat meal. Since it is generally believed that smaller LDL particles are more atherogenic , further characterization and understanding of the lipoprotein fluctuations that occur due to an acute high-fat meal may enhance our understanding of the relationship of lipoprotein particle subclasses to the increased risk for CVD.
This study differs from the majority of previous studies examining dietary influences on PPL that were conducted in smaller study populations, utilized different dietary interventions, and did not report changes in LDL particle subclasses [11, 12]. For example, Li et al  studied 33 subjects and showed that therapeutic lifestyle changes focused on diet decreased IDL among men, but not women. This is opposite to what we observed, and this is likely due to differences in the dietary intervention of Li et al  who utilized a diet low in total fat, saturated fat, and cholesterol, compared to the GOLDN intervention which was high in total fat and cholesterol. Additionally, random variation could explain differences since the Li et al  study evaluated 33 subjects compared to the 1048 reported from GOLDN.
The strengths of this study are its large sample size, the use of a standardized acute fat load, and the use of NMR technology to characterize particle size subclasses. To our knowledge, it is the largest PPL study conducted to date. Our study did not measure serum apolipoprotein B and is not a CVD outcome or mechanistic study; therefore, we do not know for certain how or why these lipoprotein particle distributional shifts occur or how they might impact CVD risk. Nonetheless, among hyper-triglyceridemic individuals, the prolonged return to baseline levels may add to an already elevated atherogenic profile .
Additionally, we did not obtain information on the activity level of enzymes and proteins that are known to be activated during the PPL response, such as CETP and HL . Specific knowledge of how these enzymes and proteins respond during an acute high-fat meal challenge would greatly enhance the understanding of our findings as well as further the understanding of lipoprotein metabolism. We only examined the acute response to 1 high-fat meal, but since humans are in a non-fasting postprandial state for a majority of the day , the changes that we demonstrated may actually never return to baseline except during the latter phases of sleep. Thus, it may be the length of time that these changes in lipoprotein particle fluctuations exist that is important in atherogenesis. Another possible mechanism for atherogenesis of the particle subclasses is the fluctuations in the TG:CE content of the particles . Since each lipoprotein particle subclass is composed of varying proportions of TG and CE, it may be that the changes in those proportions are atherogenic. Lastly, these findings may not extend to other racial groups, as our study population was all white.