Selenium-dependent down regulation of fatty acid metabolism by soluble expoxide hydrolase in inflamed macrophages
Open Access
- Author:
- Nader, Alexandra Maria
- Millennium Scholars Program:
- Microbiology (MICRB)
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisor:
- Dr. Sandeep Prabhu, Thesis Supervisor
- Keywords:
- Selenium
Inflammation
Soluble Epoxide Hydrolase - Abstract:
- The metabolism of anti-inflammatory epoxyeicosatrienoic acids (EETs) to inflammatory dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH) is a critical, but elusive pathway, which contributes to the inflammatory immune response that underlies many diseases. Selenium is an essential micronutrient that functions through its co-translational incorporation into proteins as the 21st amino acid, selenocysteine (Sec) via a highly regulated process involving a specific tRNA[Sec]. Expression of selenoproteins in murine bone marrow-derived macrophages (BMDMs) is critical to mitigate signaling pathways that culminate in the expression of inflammatory mediators upon stimulation with bacterial endotoxin lipopolysaccharide (LPS). However, the role of selenium in the regulation of sEH has not been investigated before. Therefore, we hypothesized that selenium supplementation (as selenite; 250 nM) may inhibit sEH to contribute to the alleviation of inflammation through down regulation of EET metabolism. Our results indicate that even though sEH mRNA increased in the selenium supplemented group similar to those in the selenium-adequate group (50 nM selenite; baseline selenium), the levels of sEH protein decreased only in the former group; while such a regulation was absent in the latter group. This suggests that sEH is regulated post-transcriptionally or post-translationally. Furthermore, BMDMs from Trspfl/fCreLysM mice that are unable to express selenoproteins confirmed the importance of selenoproteins in the decreased production of sEH. Our studies suggest that selenium supplementation has the ability to inhibit LPS-dependent increase in sEH and skew the metabolism of arachidonic acid metabolites towards anti-inflammatory mediators. In summary, our studies have discovered a new link to implicate the anti-inflammatory activities of selenoproteins via inhibition of sEH.