The main well-established effects of fenofibrate and fish oil on plasma lipids are their hypotriglyceridemic effects [4] and [20].

Indeed, we also found that both treatments similarly lowered serum triglyceride concentrations Z-VAD-FMK molecular weight and the number of large triglyceride–rich VLDL particles. These effects have been ascribed to an increased hepatic lipolysis and decreased lipogenesis [21] and [22], pathways which are under control of PPARα [2]. We demonstrated a small increase in HDL cholesterol concentrations after fenofibrate and fish oil treatment, reflected by increases in medium size and large size HDL particles. The increased delivery of surface remnants from the catabolism Everolimus in vivo of VLDL particles, together with a PPARα-induced expression of apoA1 and apoA2, the main apolipoproteins of HDL, may contribute to the raise in HDL cholesterol [23]. Furthermore, PPARα may stimulate reverse cholesterol transport via induction of ATP Binding Cassette protein A1 (ABCA1) [24]. Regarding the effects of fish oil and fenofibrate on triglycerides and HDL cholesterol, it is important to note that

the degree of these effects largely depend on baseline plasma lipid levels [4], [25] and [26]. In contrast to fenofibrate, fish oil increased LDL cholesterol concentrations. Others have also reported that high dose supplementation of EPA and DHA can raise LDL cholesterol by 5–10% [26]. In this respect, some groups of subjects may be more sensitive many than other groups and it has been suggested that this variability in LDL cholesterol response is related to the apoE4 variant of apolipoprotein E [27]. For fenofibrate and fish oil treatments, it has been reported that the LDL particle size changes into a more buoyant type, which may be less atherogenic [5]. In our study, however, this could not be confirmed. Fish oil increased large, small and very small LDL compared to fenofibrate. These findings seem inconsistent in relation to our observed reduction in triglycerides and increase in large

HDL particles. When plasma triglycerides are reduced, the proportion or concentration of small LDL particles is expected to be reduced and that of large HDL increased [28]. We do not have an explanation for these unexpected results. Finally, we observed a non-significant increase of fasting plasma glucose after fish oil treatment. This agrees with a meta-analysis by Balk et al. [26], who reported a very small and non-significant average net increase in fasting plasma glucose after treatment with n-3 LCPUFAs. In summary, although n-3 LCPUFAs and fenofibrate can both activate PPARα, this study in overweight and obese subjects showed that both fenofibrate (200 mg/d) and fish oil (7.2 g/d, providing 1.7 g/d EPA and 1.2 g/d DHA) treatment for 6 weeks have different effects on cardiovascular risk markers.