Down‐regulation of the hepatic selenoprotein biosynthesis machinery impairs selenium metabolism during the acute phase response in mice

Abstract

The acute-phase response (APR) is characterized by an impaired metabolism of the essential trace element selenium (Se). Moreover, low-Se concentrations correlate to mortality risk in sepsis. Therefore, we analyzed the expression of the central Se transport and storage protein selenoprotein P (Sepp1) during an APR in mice. Serum Se and Sepp1 concentrations declined in parallel after injection of lipopolysaccharide to 50 and 39% of control-injected littermates, respectively. This negative APR proceeded largely independent from hepatic Sepp1 transcript concentrations. Instead, we identified a set of hepatic transcripts involved in Se metabolism, which declined coordinately during the APR, including the selenocysteine-specific elongation factor (EFsec), selenophosphate-synthetase 2 (Sephs2), selenocysteine-tRNA[Ser]Sec synthase (SecS), and phosphoseryl-tRNA[Ser]Sec kinase (Pstk). Pstk reacted most strongly and qualified as a new limiting factor for Sepp1 biosynthesis in siRNA-mediated knockdown experiments in hepatocytes in culture. Analogous experiments were performed with mice transgenic for hepatocyte-specific human Sepp1 cDNA to verify this hypothesis. Similar kinetics and effect sizes of Sepp1 expression were observed as before in wild-type mice. We conclude that hepatic translation of Sepp1 mRNA is specifically impaired during the APR. This deficit disrupts regular Se metabolism, transport, and supply to peripheral tissues and likely aggravates the pathological status.

Reduced Serum Selenoprotein P Concentrations in German Prostate Cancer Patients

“…Both notions seem plausible and do not exclude each other. The published SNP correlation of SEPP1 genotype and increased advanced colon adenomas (14) argues for a predisposition, whereas the known decline of serum Se and serum SEPP in inflammatory conditions argues for a consequence (18,30,31). Yet, the mechanisms of action of Se in cancer prevention are far from clear.…”

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

“…The mechanisms by which this occurs are becoming clearer with recent studies. For example, there is evidence from studies in mice that acute phase response to LPS causes a decrease in selenoprotein synthesis in the liver (203). LPS led to a down-regulation of factors involved in selenoprotein synthesis, including the EFsec, selenophosphate-synthetase 2 (Sps2), Sec-tRNA…”

The role of selenium in thyroid gland pathophysiology

“…The access to mainly retrospective data, the relatively small groups of patients, and the short observation periods, as well as only single assays of selenium concentration levels, were all significant limitations in the performed studies. One should also consider the fact that low selenium concentrations may be not a cause but a result of some concomitant systemic diseases, also neoplastic, even in the effects of sustained chronic inflammation, which may impair the production of SPP1 in the liver, which, as is known, reflects the body's supply with this microelement [112][113][114][115].…”

“…Dostęp głównie do danych retrospektywnych, relatywnie małe grupy pacjentów i krótki czas obserwacji oraz pojedyncze oznaczenia zaopatrzenia w selen stanowią istotne ograniczenia przeprowadzonych badań. Należy też brać pod uwagę fakt, że niskie stężenie selenu może być nie przyczyną, lecz skutkiem występowania chorób o charakterze ogólno-ustrojowym, w tym także nowotworowych, chociażby w efekcie utrzymywania się przewlekłego stanu zapalnego, co może upośledzać produkcję selenoproteiny P w wątrobie, będącej jak wiadomo odzwierciedleniem zaopatrzeniu ustroju w ten mikroelement [112][113][114][115].…”