Postprandial hypertriglyceridemia(s): time to enlarge our pathophysiologic perspective

Postprandial hypertriglyceridemia is extremely common in patients with coronary artery disease including those with normal or close to normal fasting lipids. But is it cause or consequence, or both, or neither? Is it a fundamental pathophysiologic abnormality or merely an epidemiologic epiphenomenon? Is it only the consequence of competition between chylomicrons and very low density lipoprotein cholesterol (VLDL) for lipoprotein lipase (LPL) and therefore automatic if fasting levels of VLDL are increased or LPL reduced or are there other critical mechanisms involved? I am now persuaded that in order to understand postprandial triglyceride clearance the effectiveness of fatty acid trapping by adipose tissue must also be taken into account and if this so, the conventional framework of lipoprotein metabolism must undergo fundamental alteration. The study by van Oostrom et al. [1], which appears in this issue, presents a new experimental approach that offers further evidence it is time to alter the pathophysiologic context in which postprandial hypertriglyceridemia is dissected. Many of our experimental models have bordered on the unphysiological. Triglyceride clearance and chylomicron metabolism have been examined in detail after the ingestion of test meals, which, in their amount and content, are often unusual to say the least. Moreover, their amount is almost always standardized by body mass index (BMI). The net result is that the absolute fat load goes up as the body fat goes up, so that the acute challenge to the obese is greater than to the non-obese. This study presents an interesting alternative: determining postprandial triglyceride clearance under real life conditions by use of diurnal capillary triglyceride measurements. Their study was done in normal males and there are several ®ndings of note. First, and perhaps most important, they demonstrate that the methodology works and that subjects will cooperate. Second, even in this group of normolipidemic subjects, there was considerable variability in the capillary triglyceride level over the day and these differences appear to relate to differences in insulin sensitivity and to relative body fat. Could these differences result in increased risk of vascular disease? Of course they might, but at this stage to assume so would still be a long and risky leap of faith. Of greater immediate importance is the impetus this approach should lend to rethinking the process of postprandial lipoprotein metabolism. Certainly, the rate of triglyceride clearance correlates with the fasting triglyceride level. But what does it mean to say postprandial triglyceride clearance is delayed? That is to say, is it a unitary metabolic abnormality with similar consequences for all those who are affected? My response would be no and I would like to set forward brie ̄y the basis for that reply. Classically, chylomicron clearance occurs in two sequential steps: ®rst, there is triglyceride hydrolysis by LPL in peripheral tissues, then uptake of the remnant by the liver, and delay in this second step leading to accumulation of remnants in plasma is what is generally thought to represent the atherogenic risk of postprandial hypertriglyceridemia [2]. This may be so but I believe it is clear now that the ®rst step can also be subdivided into two critically related, sequential, but integrated processes. The ®rst of these is determined by LPL, while the second is governed by the effectiveness of fatty acid trapping by peripheral tissues. Either or both can be abnormal and the reality of that complexity is not well appreciated. The ®rst step, that is to say the LPL step, determines the rate of chylomicron hydrolysis and therefore necessarily determines the rate of triglyceride clearance from plasma. Before anything else can happen, a chylomicron particle must gain access to a suf®cient number of unoccupied LPL molecules on the capillary surface of adipose tissue or cardiac or skeletal muscle. This means that the rate of triglyceride clearance will be a function, amongst other variables, the size of these respective capillary beds, the absolute amount of functionally intact LPL, and the number of VLDL particles competing with chylomicrons for binding to LPL.