Evidence from epidemiological studies and randomised controlled trials (RCTs) suggests that replacing dietary saturated (SFAs) with unsaturated fatty acids (UFA) may have beneficial impacts on cardiometabolic disease (CMD) risk (1). However, interdisciplinary research narrowing the gap between interventional and observational evidence is lacking. Recent findings have suggested the utility of high-throughput lipidomics to identify potential CMD risk markers and provide novel aetiological insights into the relationship between dietary fat composition and CMD risk (2). Thus, this study aimed to assess the lipidome-mediated impact of replacing dietary SFAs with UFAs on CMD risk.
Plasma fatty acid (FA) concentrations among 14 lipid classes were measured using high-throughput lipidomics analyses (Metabolon, USA) in samples from the DIVAS parallel RCT (n=113), which investigated the effects of three 16-week diets enriched in SFAs (target SFA:monounsaturated fatty acids MUFA:_n-6_ polyunsaturated fatty acids PUFA ratio=17:11:4 % total energy TE), MUFAs (target SFA:MUFA:_n-6_PUFA ratio=9:19:4 %TE), or a mixture of UFAs (target SFA:MUFA:_n-6_PUFA ratio=9:13:10 %TE) on CMD risk markers such as fasting lipid profiles, and markers of inflammation, endothelial function, and arterial stiffness (3). Similar lipidomics analyses were conducted on samples from two case-cohorts from the EPIC-Potsdam prospective cohort study [n=1,707 for type 2 diabetes (T2D) and n=1,886 for cardiovascular diseases (CVD)] (2). Within-class FAs sensitive to the DIVAS dietary intervention were identified using multiple linear regression models and related to CMD risks in each EPIC-Potsdam case-cohort using multivariable Cox proportional hazard models. Finally, within-class FAs associated with changes in CMD risk markers assessed in the DIVAS study were identified using constraint-based feature selection algorithms and multiple linear regression models.
Analysis of within-class plasma FA concentrations revealed high-UFA intervention diets from the DIVAS study broadly reduced the concentrations of FAs associated with higher CVD risk, and to a lesser extent T2D risk, in the EPIC-Potsdam cohort, such as palmitic (16:0) and stearic (18:0) acids in di- and triacylglycerol, and myristic acid (14:0) in hexosylceramides, with clearer effects of the high-MUFA diet compared to the mixed-UFA. Reciprocally, the high-UFA diets increased the concentrations of FAs associated with lower CMD risk, such as erucic acid (22:1) in triacylglycerol and nervonic acid (24:1) in lactosylceramides. Furthermore, increased low-density lipoprotein cholesterol and total cholesterol concentrations were associated with a higher abundance of arachidic acid (20:0) in cholesteryl esters and diacylglycerol (p<10-3and p=0.001, respectively), whilst increased interleukin-6 and P-selectin concentrations were associated with higher proportions of arachidic acid (20:0) in mono- (p=0.008) and triacylglycerol (p=0.02).
Overall, these findings suggest a potential mediating role of plasma lipid metabolites in the association between dietary fat and CMD risk. Future research combining interventional and observational findings and investigating the identified within-class FAs is warranted to improve our understanding of dietary fat composition in CMD aetiology.
**Funding information:** This project was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) Joint Programme Initiatives (JPI) “HDHL Biomarkers: Fatty Acid Metabolism - Interlinking Diet with Cardiometabolic Health (FAME)” (Project Reference: BB/P028217/1).
**References:**
1. Scientific Advisory Committee on Nutrition: Saturated fats and health (2019)
2. Eichelmann F, Sellem L, Wittenbecher C et al. (2021), under review (Circulation)
3. Vafeiadou K, Weech M, Altowaijri H et al. (2015) Am J Clin Nutr 102:1, 40-48

The impact of dietary saturated fat replacement with unsaturated fat on the plasma lipidome and cardiometabolic disease risk

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