Fish oil inhibits Δ6 desaturase activity in vivo: Utility in a dietary paradigm to obtain mice depleted of arachidonic acid

In mice that were alternately fasted and then refed an essential fatty acid-deficient (EFAD) diet, there was a rapid and substantial decline in tissue n-3 and n-6 polyunsaturated fatty acids (PUFAs) and a corresponding increase in n-9 fatty acids. Combined in vivo activities of Δ6 + Δ5 desaturates were quantified directly by measuring the conversion of ¹⁴C-linoleic acid (intraperitoneal injection) to ¹⁴C-arachidonic acid in liver lipids. Δ5 desaturase activity was quantified by measuring the conversion of ¹⁴C-dihomo-γ-linolenic acid (intraperitoneal injection) to ¹⁴C-arachidonic acid in liver lipids. The combined Δ6 + Δ5 desaturase activities in EFAD mice was very similar to that in chow-fed control mice (35% vs. 33% conversion of ¹⁴C-linoleic acid to ¹⁴C-arachidonic acid, respectively). Subsequent refeeding of EFAD mice with an EFAD diet supplemented with corn oil restored tissue n-6 PUFA levels, but did not alter Δ6 + Δ5 desaturase activities (33%). In contrast, subsequent refeeding of EFAD mice with a fish-oil supplemented diet markedly inhibited Δ6 + Δ5 desaturase activities (7%). Fatty acid analysis of the livers from the fish-oil-fed mice showed that there was a depletion of the n-6 PUFAs, linoleic acid, and arachidonic acid, and an increase in the n-3 PUFAs, eicosapentaenoic acid (20:5 n-3) and docosahexaenoic acid (22:6 n-3). The inhibition of Δ6 + Δ5 desaturase activities was also maintained in EFAD mice fed a 1:1 mixture of fish oil:corn oil. As a consequence, a unique fatty acid composition in liver and plasma was obtained in which arachidonic acid was selectively depleted, whereas linoleic acid and n-3 PUFAs wee increased. Δ5 desaturase activity was not affected by any of the fasting/refeeding paradigms. The data demonstrate that dietary n-3 PUFAs negatively regulate the in vivo synthesis of n-6 PUFAs at the level of the Δ6 desaturase. The inhibition of Δ6 desaturase activity by n-3 PUFAs provides a basis for a unique dietary route to selectively reduce tissue arachidonic acid, while providing sufficient linoleic acid, an essential fatty acid, to support normal cellular metabolism. This dietary paradigm may be effective in attenuating diseases characterized by excessive production of arachidonic acid-derived eicosanoids.