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The Benefits of Fish Oil

Both 3 and 6 fatty acids are essential in the diet. American diets have a surplus of 6 vegetable oil fatty acids and a relative lack of fish oil 3 fatty acids. Increased consumption of fish oil promotes cardiovascular health, is anti-inflammatory, and may protect against colon cancer. The molecular basis for the various health benefits of 3 fatty acids is unknown. Prostaglandins (PGs) and thromboxanes (Txs) are produced in vivo from both the 6 fatty acid arachidonic acid (AA) and the 3 fatty acid eicosapentaenoic acid (EPA), but the PGs and Txs formed from EPA and AA are slightly different. Certain beneficial effects of fish oil may result from altered PG metabolism caused by increases in EPA to AA ratios.

In this Paper of the Week, Masayuki Wada, Cynthia DeLong, and colleagues charted the specificities of the prostaglandin biosynthetic enzymes and receptors toward AA-derived versus EPA-derived substrates and products. Their results predict that diets leading to increased phospholipid EPA to AA ratios would dampen net prostanoid signaling through cyclooxygenase-1 pathways involving PGs and Txs. In contrast, cyclooxygenase-2 pathways that form pro-inflammatory and anti-thrombotic PGs would be much less affected. These results are consistent with EPA mediating cardiovascular benefits of fish oil by altering PG metabolism but suggest that there are processes not involving PGs that mediate anti-inflammatory effects of fish oil.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 22254-22266

The Transcription Factor Two-step

The interferon regulatory factor 3 (IRF-3) transcription factor is a key component of the innate antiviral response. It is activated by phosphorylation mediated as part of a signaling cascade by the kinases TBK1 and IKK. Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure, allowing interaction with the co-activators CBP/p300. Although the central role of IRF3 in regulating the innate immune response has been increasingly recognized in recent years, there remain some disparities in the interpretation of the biochemical and structural literature concerning the activation mechanism for IRF3.

Two-step model of IRF-3 activation.

In this Paper of the Week, Daniel Panne and colleagues provide evidence for a two-step model for the mechanism of IRF3 activation by phosphorylation. Using purified proteins they show that TBK1 can directly phosphorylate full-length IRF-3 in vitro. Phosphorylation at residues in site 2 (Ser³⁹⁶ to Ser⁴⁰⁵) of IRF-3 alleviates autoinhibition to allow interaction with CBP and facilitates phosphorylation at site 1 (Ser³⁸⁵ or Ser³⁸⁶). Phosphorylation at site 1 is, in turn, required for IRF-3 dimerization.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 22816-22822

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