Abstract
Oxylipins are bioactive lipids formed by the monooxygenation of polyunsaturated fatty acids (PUFA). Eicosanoids derived from arachidonic acid (ARA) are the most well-studied class of oxylipins that influence brain functions in normal health and in disease. However, comprehensive profiling of brain oxylipins from other PUFA with differing functions, and the examination of the effects of dietary PUFA and sex differences in oxylipins are warranted. Therefore, female and male Sprague-Dawley rats were provided standard rodent diets that provided additional levels of the individual n-3 PUFA α-linolenic acid (ALA), eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or the n-6 PUFA linoleic acid (LNA) alone or with ALA (LNA + ALA) compared to essential fatty acid-sufficient control diets. Oxylipins and PUFA were quantified in whole brains using HPLC-MS/MS and GC, respectively. Eighty-seven oxylipins were present at quantifiable levels: 51% and 17% of these were derived from ARA and DHA, respectively. At the mass level, ARA and DHA oxylipins comprised 81-90% and 6-12% of total oxylipins, while phospholipid ARA and DHA represented 25-35% and 49-62% of PUFA mass, respectively. Increasing dietary n-3 PUFA resulted in higher levels of oxylipins derived from their precursor PUFA; otherwise, the brain oxylipin profile was largely resistant to modulation by diet. Approximately 25% of oxylipins were higher in males, and this was largely unaffected by diet, further revealing a tight regulation of brain oxylipin levels. These fundamental data on brain oxylipin composition, diet effects, and sex differences will help guide future studies examining the functions of oxylipins in the brain.
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Key Points
Oxylipins are bioactive lipid mediators synthesized from polyunsaturated fatty acids (PUFA) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) monooxygenase activities. They are major regulators of physiological processes and inflammatory responses in tissues but are relatively less characterized in the brain. Few studies examining sex differences in a small number of brain oxylipins have been reported. There are also few studies of sex differences on the oxylipin profile in other tissues, but these indicate that oxylipins are generally higher in males in kidneys, liver, and serum and higher in females in heart and adipose tissues. Therefore, the objectives of the current study were (1) to provide fundamental data on the rat brain oxylipin profile, (2) to investigate the effects of dietary n-3 and n-6 PUFA on this profile, and (3) to examine sex differences in this profile.
The current study provides fundamental data on the rat whole brain oxylipin profile. These data show that while there is more DHA than ARA in the brain, the oxylipins in the brain are primarily derived from arachidonic acid – ARA. This is not simply a function of more ARA oxylipins being screened for, as the mass of each ARA oxylipin was always higher than the mass of its DHA analog [e.g. 15 hydroxyeicosatetraenoic acid (15-HETE) vs 17-HDoHE]. This preponderance (>80% of total) of ARA oxylipin mass in the brain differs from the pattern observed in other tissues in these rats. In conclusion, this study provides novel fundamental data on the rat brain oxylipin profile and the modulation of oxylipin levels in male and female rats provided increased levels of dietary n-3 and n-6 PUFA. This provides impetus for further studies on the many oxylipins detected, but for which no function in the brain has yet been reported. Compared to other tissues, the brain has a much higher proportion of ARA oxylipins despite being present at lower levels than DHA. The brain is also much more resistant to dietary modulation of its oxylipins. Oxylipins displaying sex differences were mostly higher in male rats, and diet also did not alter these differences, further revealing tight control of oxylipin levels in the rat brain.