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The influence of dietary n-6 polyunsaturated fats on the inflammatory state of macrophages

University of British Columbia

Dietary n-6 polyunsaturated fatty acids (n-6 PUFA) like linoleic acid (LA) are linked to inflammatory diseases. It is believed that arachidonic acid (ARA), generated from LA is primarily responsible for such inflammation. However, studies show that dietary LA does not raise ARA in vivo and chronic disease patients often demonstrate low serum ARA. Thus, I hypothesized that LA, the parent n-6 PUFA causes inflammation independent of ARA. First, I show that adding LA activates RAW 264.7 macrophages (MФs) which demonstrates increased mitochondrial respiration, glucose uptake, cholesterol storage and reactive oxygen species (ROS) production compared to oleic acid (OA), a monounsaturated fatty acid (MUFA). Interestingly though, feeding a diet rich in LA (corn oil, CO; 54% LA) or OA (olive oil, OO; 54% OA) for six weeks in mice did not alter the inflammatory state of macrophages (PMФs). However, when I fed these diets to ELOVL5 +/- mice, which were deficient in an enzyme that allows the conversion of LA to ARA and therefore has higher LA, the accumulation of LA in PMФs demonstrated proinflammatory effects. Taken together, I conclude that LA accumulation in the short-term does not activate macrophages but long-term accumulation of LA mediated by congenital ELOVL deficiency does. In addition, feeding a MUFA diet did not counteract the activation of macrophages or higher LA levels in ELOVL5 ⁺/⁻ mice. Thus, I conclude that dietary MUFA cannot overcome a genetic deficiency of ELOVL5, indicating the critical role of this enzyme in maintaining PUFA levels in macrophages. Thus, my thesis clarifies the crucial role of ELOVL5 in the PUFA bioconversion pathway and its central importance in regulating the pro-inflammatory properties of n-6 PUFA. In the current milieu of high LA in our diet, activation of ELOVL5 and clearance of LA could be used as a therapeutic target against inflammation.

Text

2019-07-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71127

Biochemistry and Molecular Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/