Discussion
CMD, T2D, TG
CVD, REGRESSION, SECONDARY, ARTERIAL STIFFNESS
In this secondary analysis, lipidome-wide screening revealed broad reductions in SFA along with increased MUFA and PUFA concentrations across several plasma lipid classes (i.e., sphingolipids and glycerolipids) following the exchange of dietary SFAs with UFAs for 16 wk. These results might be partly explained by the absorption of dietary UFAs throughout the MUFA-rich and PUFA-rich dietary interventions, since glycerolipids are common FA storage structures found within lipoprotein particles such as chylomicrons [Other consequences of the DIVAS MUFA-rich diet included lower long-chain FA concentrations in plasma sphingolipids such as 18:1, 20:1, and 22:1 in CER and HCER after intervention compared to the SFA-rich diet. Although decreased MUFA concentrations in these lipid classes following the replacement of dietary SFAs with MUFAs might seem counterintuitive, these results are in line with experimental findings, which suggested that SFAs may be used as precursors for the first step of the endogenous synthesis of 16:1 and 18:1 sphingolipids catalyzed by the serine palmitoyltransferase enzyme [Coordinated CLP analyses between DIVAS and EPIC-Potsdam revealed that both DIVAS UFA-rich diets reduced plasma concentrations of 15:0, 17:0, and 18:0 in glycerolipids (i.e., DAG and TG), which were associated with higher CVD risk in EPIC-Potsdam. Previous epidemiological studies on circulating odd-chain SFAs, used as biomarkers of dairy consumption [Overall, the DIVAS dietary interventions seemed less efficient in increasing plasma within-class FAs that are inversely associated with T2D risk. However, the MUFA-rich dietary intervention seemed to decrease the plasma levels of 16:0 in DAG and TG, along with 18:0 in DAG and SM, which were directly associated with T2D risk in EPIC-Potsdam [In the DIVAS study participants, we identified that higher plasma levels of CE (18:0) and TG (12:0) were associated with higher LDL cholesterol, which was independent of the intervention group and other potential confounding factors. These results support previously described general lipid compositions of LDL particles, which contain ∼42% of CE and 6% of TG (wt/wt) [The strengths of this study include its extensive panel of investigated lipids, which were aggregated into within-class FAs to facilitate the interpretability of the findings. Second, this coordinated analysis between DIVAS and EPIC-Potsdam provided novel insights, bridging the gap between data from dietary intervention and prospective cohort studies. Finally, this analysis benefited from strong methodological approaches in the identification of lipidomic predictors of CMD risk and associated biomarkers by adjusting Cox proportional hazard models and linear regression models with a wide range of potential confounders, along with using crossvalidation methods and corrections from multiple testing. Nonetheless, some limitations of this study need to be acknowledged. First, although the CLP provided details on the acyl chains within lipid classes, there was no information on the location of the configuration of double bonds in FAs (i.e., cis or trans). Second, plasma-free FA levels were not available. Third, risk of lipid degradation and oxidation in plasma samples cannot be entirely ruled out, although the DIVAS samples had been stored at −80 °C and were not thawed until analysis [In conclusion, the replacement of dietary SFAs with UFAs in the DIVAS RCT led to modifications of the plasma lipidome metabolites among UK adults at the moderate CVD risk. Furthermore, our findings suggest that the associations between lipid metabolites and markers of CMD risk may be specific to certain FAs and lipid classes. Specifically, some sphingolipids and phospholipids may be related to novel CVD risk markers, including endothelial function, arterial stiffness, and ambulatory blood pressure. Finally, the coordinated lipidome-wide plasma screening performed in EPIC-Potsdam suggested that the changes in plasma lipid metabolites observed after the replacement of dietary SFAs with UFAs may be beneficially associated with long-term CMD risk. Overall, these results concur with current evidence on the benefits of replacing dietary SFAs with UFAs for CMD risk prevention and contribute to the evidence base on the role of lipid metabolites in CMD etiology.