Biochem. J. (2008) 409
(741–749) (Printed in Great Britain)
Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice
Kostja RENKO*†1, Margarethe WERNER*1, Ingrid RENNER-MÜLLER‡, Trevor G. COOPER§, Ching Hei YEUNG§, Birgit HOLLENBACH†, Marcus SCHARPF∥, Josef KÖHRLE†, Lutz SCHOMBURG† and Ulrich SCHWEIZER*†2
*Neurobiology of Selenium, Neuroscience Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany, †Institute for Experimental Endocrinology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany, ‡Institute of Molecular Animal Breeding and Biotechnology, Genecenter of the Ludwig-Maximilians University, Munich, Germany, §Institute of Reproductive Medicine of the University Clinic, Münster, Germany, and ∥Institute of Pathology, Eberhard Karls Universität, Tübingen, Germany
SePP (selenoprotein P) is central for selenium transport and distribution. Targeted inactivation of the Sepp gene in mice leads to reduced selenium content in plasma, kidney, testis and brain. Accordingly, activities of selenoenzymes are reduced in Sepp−/− organs. Male Sepp−/− mice are infertile. Unlike selenium deficiency, Sepp deficiency leads to neurological impairment with ataxia and seizures. Hepatocyte-specific inactivation of selenoprotein biosynthesis reduces plasma and kidney selenium levels similarly to Sepp−/− mice, but does not result in neurological impairment, suggesting a physiological role of locally expressed SePP in the brain. In an attempt to define the role of liver-derived circulating SePP in contrast with locally expressed SePP, we generated Sepp−/− mice with transgenic expression of human SePP under control of a hepatocyte-specific transthyretin promoter. Secreted human SePP was immunologically detectable in serum from SEPP1-transgenic mice. Selenium content and selenoenzyme activities in serum, kidney, testis and brain of Sepp−/−;SEPP1 (SEPP1-transgenic Sepp−/−) mice were increased compared with Sepp−/− controls. When a selenium-adequate diet (0.16-0.2 mg/kg of body weight) was fed to the mice, liver-specific expression of SEPP1 rescued the neurological defects of Sepp−/− mice and rendered Sepp−/− males fertile. When fed on a low-selenium diet (0.06 mg/kg of body weight), Sepp−/−;SEPP1 mice survived 4 weeks longer than Sepp−/− mice, but ultimately developed the neurodegenerative phenotype. These results indicate that plasma SePP derived from hepatocytes is the main transport form of selenium supporting the kidney, testis and brain. Nevertheless, local Sepp expression is required to maintain selenium content in selenium-privileged tissues such as brain and testis during dietary selenium restriction.
Key words: brain, fertility, glutathione peroxidase, nutrition, selenium, thioredoxin reductase.
Abbreviations used: ApoER2, apolipoprotein E receptor 2; BBB, blood–brain barrier; GPx, glutathione peroxidase; rpm, rounds per min; RT, reverse transcription; Sec, selenocysteine; SECIS, selenocysteine insertion sequence; SePP, selenoprotein P; Sepp, mouse SePP gene; SEPP1, human SePP gene; Sepp−/−;SEPP1, SEPP1-transgenic Sepp−/−; Trsp, Sec-specific tRNA[Ser]Sec; TTR, transthyretin; Txnrd, thioredoxin reductase; UTR, untranslated region.
1These authors contributed equally to this study.
2To whom correspondence should be addressed (email ulrich.schweizer@charite.de).
Received 28 August 2007/24 October 2007; accepted 26 October 2007
Published as BJ Immediate Publication 26 October 2007, doi:10.1042/BJ20071172
© The Authors Journal compilation © 2008 Biochemical Society
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