Use of transcriptomics to explore the role of dietary fat on cardiovascular disease risk

Abstract

Replacing saturated fatty acids (SFA) with polyunsaturated fatty acids (PUFA) is associated with reduced cardiovascular disease (CVD) risk. This effect is largely mediated through lowering of serum low-density lipoprotein (LDL) cholesterol, which is a well-characterized CVD risk factor. Intake of n-3 PUFAs may also lower serum triglycerides (TG), and is proposed to have anti-inflammatory effects. However, the molecular mechanisms that link dietary fatty acids and such physiological effects are not fully understood. The overall aim of this thesis was to explore the molecular mechanisms underlying the effect of dietary fat quality on CVD risk by use of transcriptome profiling of peripheral blood mononuclear cells (PBMC) in human studies. In a cross-sectional study, Larsen et al. found that plasma SFA to PUFA ratio was associated with a higher number of differently expressed genes than n-6 and n-3 PUFA levels, and that several of these genes were related to cholesterol homeostasis. Further, in a dietary intervention study, they found that TG responders (ΔTG ≤ −20 %) and non-responders (−20 % < ΔTG < +20 %) to n-3 PUFA supplementation had different baseline gene expression profiles and differently altered gene expression profiles and pathways after seven weeks. Finally, in a randomized controlled dietary intervention study, they found that replacing dietary SFAs with PUFAs for eight weeks favourably altered the expression of several genes associated with processes related to CVD risk, and that the change in expression of some of these genes were correlated to change in serum cholesterol levels. Furthermore, several pathways were differently altered between the two intervention groups. In conclusion, the findings in this thesis support that fat quality is associated with PBMC gene expression, which may contribute to extend our understanding of how dietary fat affects CVD risk and why individuals respond differently to n-3 PUFA intake.