title: 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.
authors.affiliation: Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
authors.forename: Kostja
authors.initials: K
authors.lastname: Renko
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hofmann
authors.forename: Mette
authors.initials: M
authors.lastname: Stoedter
authors.forename: Birgit
authors.initials: B
authors.lastname: Hollenbach
authors.forename: Thomas
authors.initials: T
authors.lastname: Behrends
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012643:Selenium / Q000378:metabolism*; D051149:Selenoprotein P / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D051149:Selenoprotein P; D048052:Mitogen-Activated Protein Kinase 3; D012643:Selenium