On the Mechanisms by Which Human Apolipoprotein A-II Gene Variability Relates to Hypertriglyceridemia * Response
A recent issue of Circulation contained an interesting study by van't Hooft et al 1 reporting a novel functional polymorphism (a T to C substitution at position Ϫ265) in the promoter region of the apolipoprotein A-II (apoA-II) gene. ApoA-II is the second quantitatively major protein component of HDL. In the above-mentioned study, the Ϫ265C allele was associated with decreased plasma apoA-II concentration, enhanced postprandial metabolism of large VLDL, and decreased waist circumference in
... y 50-year-old men. 1 Important and rather surprising advances in our understanding of the role of apoA-II have been reported recently and have mainly been produced by analyses of genetically modified mice. 2 In line with the findings of van't Hooft et al, 1 these advances revealed a consistent relationship of apoA-II with non-esterified fatty acids (NEFA) and VLDL triglyceride plasma concentrations. However, whether apoA-II variability causes increased VLDL synthesis, decreased VLDL catabolism, or both remains a matter of controversy. 2 We recently studied human apoA-II-transgenic(Tg)-mice 2 and control C57BL/6 mice fed a Western high-fat diet (TD 88137, Harlan Teklad) for 32 weeks. As in previous studies, 2 fasting cholesterol, triglycerides, and NEFA concentrations were increased in human apoA-II-Tg-mice. We performed oral fat tolerance tests in these mice after oral administration of 100 L of olive oil. The area under the curve (AUC) of triglyceride concentrations in human apoA-II-Tg-mice was significantly increased compared with that of control mice (18.5Ϯ6.1 versus 5.4Ϯ1.2; PϽ0.05). The AUC increase in postprandial triglycerides was due to an increased secretion rate (11.9Ϯ8.7 mol triglycerides · h Ϫ1 · Kg Ϫ1 in transgenic mice versus 1.5Ϯ0.2 mol triglycerides · h Ϫ1 · Kg Ϫ1 in control mice; PϽ0.05) because triglyceride catabolism did not differ (0.85Ϯ0.08 pools/h in transgenic mice versus 0.99Ϯ0.12 pools/h in control mice). These data contrast with the interpretation of van't Hooft et al, 1 who suggested that apoA-II polymorphism is associated with enhanced postprandial VLDL clearance. In our opinion, the effect of the human apoA-II polymorphism found in their study could also be reinterpreted as the result, at least in part, of decreased postprandial VLDL synthesis which could be due to, for example, decreased postprandial NEFA levels in plasma of individuals with the Ϫ265C allele. In this context, we would like to know whether the authors measured postprandial NEFA and, if so, what the results were. Further, we are curious as to whether they have any other data with regard to this study that rule out the possibility of decreased VLDL synthesis being a mechanism implicated in their findings.