Metabolites of arachidonic acid acting in the small intestine mediate systemic and vascular inflammation in LDLR null mice (832.13)

We previously reported that a Western Diet increased levels of free arachidonic acid (AA) and its metabolites in the small intestine and plasma of LDLR null mice and increased plasma levels of serum amyloid A (SAA). To determine the role of AA metabolites in initiating inflammation, LDLR null mice on a chow diet were or were not administered 15‐hydroxyeicosatetraenoic acid (15‐HETE) at a dose of 5 μg/day (mixed into the chow) or the mice received 5 μg/day subcutaneously (SQ). After two weeks the mice were bled, perfused with saline to remove any remaining blood and the heart was harvested. Plasma levels of SAA were determined by ELISA and levels of free AA and its metabolites were determined in plasma by LC‐ESI‐MS/MS. Plasma SAA levels increased from 6.4 ± 1.9 ug/mL on chow without 15‐HETE to 15 ± 7 ug/mL with oral 15‐HETE (p<0.0001) and 15 ± 8 µg/mL with SQ (p = 0.0004). Plasma levels of free AA increased from 2435 ± 420 ng/mL on chow to 3274 ± 517 ng/mL with oral 15‐HETE (p<0.0001) and 2712 ± 479 ng/mL with SQ (p = 0.001). Three hours after the last SQ dose, plasma 15‐HETE levels were 0.9 ± 0.4 ng/mL on chow, 2.7 ± 1.5 ng/mL after oral (p<0.0001) and 1.5 ± 0.3 ng/mL after SQ 15‐HETE (p<0.0001). 5‐HETE and 12‐HETE levels also increased (p<0.001) and the magnitude of the changes were similar whether the 15‐HETE was administered orally or SQ. We conclude i) 15‐HETE administration increases plasma SAA, and free AA levels to a similar degree whether administered orally or SQ; ii) These results suggest that AA metabolites such as 15‐HETE can act in the small intestine to regulate systemic inflammation. Grant Funding Source : NIH