Project Summary
Epidemiological studies suggest that the consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs)
derived from fish oil, mainly consisting of eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid
(DHA; 22:6 n-3), is associated with lower cardiovascular risk. However, interventional clinical trials aimed at
reducing cardiovascular incidents by supplementation with n-3 PUFAs have yielded inconsistent results. The
mechanisms responsible for the benefit of n-3 PUFAs on cardiovascular risk are still not completely understood.
Mounting evidence suggests that in addition to lowering triglycerides, the triglyceride-independent effects of n-3
PUFAs also contribute to their cardiovascular benefits. It is likely that differential effects of EPA and DHA also
contribute to the inconsistent clinical results. A head-to-head comparison of the biological effects of EPA and
DHA in a relevant population is urgently required. Based on our preliminary data, we hypothesize that EPA and
DHA have differential effects on thrombogenesis in patients with atherogenic dyslipidemia that are mediated by
the modification of HDL particle function. We propose a proof-of-concept clinical study comparing the biological
effects, particularly the thrombogenesis and antiplatelet effects, of an adequate dose of EPA and DHA head-to-
head in atherogenic dyslipidemia subjects. We will also examine the mechanism of how HDL particles mediate
these antithrombotic effects. Specific Aim1: To test the hypothesis that EPA and DHA differentially affect platelet
activation and thrombosis in vivo in subjects with atherogenic dyslipidemia. Human subjects with atherogenic
dyslipidemia will be randomized to dietary supplementation with four grams of either EPA or DHA n-3 PUFAs in
a single-blinded fashion for eight weeks. At baseline and after the supplementation, various markers of
thrombogenesis will be assessed. Specific Aim 2: To test the hypothesis that the effects of n-3 PUFAs on
platelets are mediated by the modulation of HDL particle function. At baseline and post n-3 PUFA
supplementation, HDL particle composition and HDL functions will be analyzed, respectively. We will further test
our hypothesis mechanistically in an HDL-deficient mouse model. HDL-dependent bioactive lipid production will
be characterized in both human and mouse studies. These studies will provide insight into a new paradigm of
understanding the puzzling clinical evidence of n-3 PUFAs and may ultimately lead to the development of novel
therapies to combat cardiometabolic risk.