Postprandial lipoprotein metabolism--pivot or puzzle?

The hypothesis that postprandial increases in blood lipids and lipoproteins play a causal role in the etiology of cardiovascular disease (CVD) is now 28 y old (1). It states that atherosclerosis is produced largely by triacylglycerol-rich lipoprotein particles that circulate the first few hours after a meal but are not seen in the fasting state in healthy persons. The hypothesis has generated much research but as yet no definitive conclusions. A large number of studies show that clearance of postprandial lipoproteins is slower in patients with diabetes or CVD and that it is associated with several changes in the blood lipoprotein profile, such as low HDL-cholesterol concentrations, high fasting triacylglycerol concentrations, elevated apolipoprotein C-III, and the presence of small, dense LDL particles (2). However, large prospective studies are needed to establish the independent predictive value of postprandial lipids for CVD endpoints. Ideally, such studies should quantify the triacylglycerol response over a fixed number of hours after a standardized meal in thousands of people and monitor the incidence of CVD during many years of follow-up. This is nearly unfeasible because of the huge amounts of labor and cost needed to perform standardized meal tests on a very large scale. Alternatives are to measure the characteristics of lipoproteins that are pronounced in the postprandial state or that reflect a slowed triacylglycerol metabolism. However, lipoprotein metabolism is very complex and not completely understood, and there is no consensus on which changes in lipid composition, size, and density or in apolipoproteins are most relevant. Many studies have focused on small, dense LDL particles, but most prospective studies have not shown their additive predictive value over and above those of standard lipid risk factors, ie, LDL cholesterol, HDL cholesterol, fasting triacylglycerols, and apolipoprotein B (3). Another approach is to focus on the apolipoprotein constituents of triacylglycerol-rich lipoproteins particles that affect their metabolism, such as apolipoproteins C and E. One prospective, nested, case-control study in diabetic patients with previous myocardial infarction showed that fasting apolipoprotein CIII was a strong independent predictor of coronary events during 5 y of follow-up (4). Postprandial lipoprotein clearance is also closely linked to fasting triacylglycerol concentrations. As their independent predictive value for CVD endpoints is established (5), fasting triacylglycerols may be seen as the currently most relevant indicator of postprandial lipemia. If we assume that the postprandial lipid response is an important indicator of CVD risk, then what is the role of diet? Most studies have focused on dietary fatty acids. In this issue of the Journal, Hilpert et al (6) report the postprandial effects of test meals with 50 g of fat differing in monounsaturated fatty acids (MUFA), the n 3 fatty acid -linolenic acid (ALA), and the n–3 very-long-chain polyunsaturated fatty acids (VLCPs) on apolipoprotein-defined lipoprotein subclasses in 15 diabetic patients. They found that a meal containing 4 g VLCPs significantly attenuated the postprandial increase in the apolipoprotein B and C–containing lipoprotein fraction compared with a meal containing MUFA only. The treatments did not significantly affect 3 other postprandial apolipoprotein B–containing lipoprotein subfractions or total apolipoprotein B, although the meal with 2.8 g ALA rather than the VLCP meal tended to attenuate the apolipoprotein B, C, and E–containing lipoprotein fraction. Postprandial triacylglycerol concentrations, which were tested in the same subjects and reported in an earlier article by the same study group (7), were not significantly lower after the VLCP meal. Thus, results on markers of triacylglycerol-rich lipoproteins were not consistent, but they suggest that different unsaturated fatty acids may have differential effects on postprandial lipoprotein metabolism. Caution is needed, because testing multiple outcomes in a small study can easily produce chance findings. Further studies should have a larger sample size and also determine the effects of longer-term VCLP intakes on fasting apolipoprotein C concentrations, because these may have predictive potential (4). Hilpert et al extend their findings by relating the postprandial apolipoprotein changes to the acute effects of the test meals on vascular reactivity, which were reported earlier (7). The postprandial change in apolipoprotein B and C–containing lipoproteins after the VLCP-rich test meal were, to some extent, inversely associated with the postprandial change in flowmediated dilatation (FMD) of the brachial artery. The authors suggest that their findings provide a potential mechanism for the atherogenic effects of apolipoprotein B and C–containing lipoproteins. This inference needs some comments. First, the value of post hoc cross-sectional analyses in a study with only 15 subjects can be questioned. Second, it could be that postprandial lipid and endothelial responses are both linked to a common underlying factor or to some phenotypical characteristic of the subjects—perhaps the degree of insulin resistance of the subjects or low-grade inflammatory processes triggered by postprandial metabolism. Third, the acute effects of fatty acid intakes on