Commentary: Chylomicronaemia, fat tolerance and atherosclerosis—a commentary on a landmark paper

In the 1940s, the association between arterial wall accumulation of cholesterol and lipid substances forming the basis for the then acknowledged foam cell formation was still rather anecdotal, and the research field was lacking a systematic approach to search for the link between blood lipids and atherosclerosis. Although it had been acknowledged that raised blood cholesterol was seen in some patients with myocardial infarction, it was at that time also clear that the disease could occur in people with seemingly ‘normal’ cholesterol. Therefore, in 1947, John Moreton proposed a novel link between the very obvious opacity of serum observed soon after oral fat intake and the build-up of atherosclerosis.1 This idea arose from the key observations that chylomicrons were large enough to scatter light, thereby giving the milky appearance of in plasma, enabling a technology (nephelometry, which gives a quantitative value for light scatter) to estimate the presence of chylomicrons in serum, and that repeated intravenous injections of other macromolecules into dogs could lead to deposition of the macromolecule in question in the arterial wall.2 In order to systematically approach the problem, Moreton evaluated the use of a standardized oral fat tolerance test which simply consisted of a body surface-adjusted dose of dairy cream.3 He discovered that nephelometry applied to postprandial serum blood gave him a semi-quantitative estimation of large lipoproteins through their light-scattering properties. He concluded that the appearance in serum of the light-scattering chylomicrons was proportional to the magnitude of fat intake. The test was also shown to be reproducible within an individual. Importantly, people with pre-existing hyperlipidaemia had a vastly exaggerated blood lipid response to the oral fat tolerance test. Moreton’s work, and the interpretations he made, will need to be put in context of what was then known, as well as the methodological techniques available at that time. For example, Moreton’s concept was put forward before the serum lipoprotein fractions were defined, either by lipoprotein particle size or their lipid composition. Also, at this point in time it was not clear how triglycerides were eliminated from blood—the function and characteristics of the key enzyme, lipoprotein lipase, was unravelled over a time period 10–20 years later. Routine measurements of serum triglyceride concentrations came about 10 years later. Ironically, Moreton hinted at the very association that has discouraged clinical researchers in later years from adopting an oral fat tolerance test as a tool for cardiovascular risk stratification of people with postprandial hyperlipidaemia. Indeed, he observed that higher baseline blood lipid concentrations lead to an exaggerated postprandial response. In later years it has been demonstrated over and over again that the correlation between fasting plasma triglyceride concentrations and postprandial lipid responses are very tight indeed. Although this gives a good reason for the futility of the clinical use of an oral fat tolerance test (a postprandial response is likely to be well predicted from the fasting triglyceride concentration), it certainly does not exclude the possibility that lipoproteins generated in the postprandial state are more atherogenic than those in the fasted state. With today’s knowledge, what do we think about the association between chylomicronaemia, fat tolerance and atherosclerosis? If we start with the idea that chylomicrons, or their immediate remnant lipoprotein particles, are particularly atherogenic, this is still a rather controversial supposition. We now know that chylomicrons and chylomicron remnants are very transient in blood, with half-lives ranging from 5 from 15 minutes. Also, the particle concentrations of chylomicrons and chylomicron remnants are extremely low, i.e. in the range of 1/10 to 1/100 of other potentially atherogenic lipoproteins such as very low density lipoproteins (VLDL) and LDL. The fact that patients with type I hyperlipidaemia, who exhibit constant and extreme chylomicronaemia, are not at any particularly elevated risk of cardiovascular disease is a pertinent reminder that the hypothesis might be weak. The overwhelmingly largest proportion of chylomicron particles is rapidly removed from plasma, primarily by the liver, when they are still very large remnants.4 Also, detailed studies on how lipoproteins of different sizes may penetrate the vascular endothelium have suggested that triglyceride-rich lipoproteins, much smaller than chylomicrons and most chylomicron remnants, are effectively excluded from deposition beneath the vascular endothelium due to size.5 All this suggests a very limited endothelial exposure to the particles Moreton considered most atherogenic. However, it should be acknowledged that the very preferential metabolism of chylomicrons has secondary effects on a number of other potentially atherogenic lipoproteins. First, there is a very significant cholesterol enrichment of apoB-100 containing VLDL seen in postprandial state.6 Second, the cholesteryl ester transfer protein (CETP)-mediated lipid exchanges involving LDL are enhanced in the postprandial state, which increases the generation of small dense LDL. As these mechanisms are directly related to metabolic events in the postprandial state and involve potentially atherogenic lipoproteins at much higher blood concentrations than chylomicrons or their remnants, they are better aligned with the concept of apoB and atherogenic particle number being a major determinant of the ‘lipid’ risk.7 Moreton put his finger on the most active and easily visible aspects of the plasma triglyceride transport system and its relationship to atherosclerosis. For quite some time the relationship between plasma triglycerides and cardiovascular risk was controversial, and only recently has this discussion begun to settle. It is now clear that a major contributing factor to the conflicting literature on triglycerides and cardiovascular risk was in part due to the heterogeneity of triglyceride-rich lipoproteins and the rapidly changing plasma triglyceride concentrations, together with questionable statistical adjustments for HDL. The intricacies of evaluating triglycerides as a cardiovascular risk factor was outlined already 25 years ago.8 It was not until prospective, long-term and large-scale studies using appropriate statistical models identified triglycerides as a strong and independent cardiovascular risk factor that we got robust evidence for the concept.9 Additional proof of a causal link between raised plasma triglycerides and cardiovascular risk came with the large-scale genome-wide studies enabling Mendelian randomization.10 These complex arguments supporting the strong relationship between plasma triglycerides and cardiovascular disease have recently been summarized by Nordestgaard et al.11 Moreton was certainly ahead of his time, and it is ironical that his visionary contributions have not been more widely recognized; as of September 2015, his statement paper in Science1 has only attracted 110 references over 68 years, whereas the methodological paper in the international Journal of Laboratory and Clinical Medicine3 has been referred to 94 times. Conflict of interest: None declared.