Hepatic selenoprotein P (Sepp) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice
Résumé
Selenoprotein P (SePP) is central for selenium (Se) transport and distribution. Targeted inactivation of the Sepp gene in mice leads to reduced Se content in plasma, kidney, testis, and brain. Accordingly, activities of selenoenzymes are reduced in Sepp -/-} organs. Male Sepp -/-} mice are infertile. Unlike Se deficiency, Sepp-deficiency leads to neurological impairment with ataxia and seizures. Hepatocyte-specific inactivation of selenoprotein biosynthesis reduces plasma and kidney Se levels similar 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 to 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. Se content and selenoenzyme activities in serum, kidney, testis, and brain of Sepp -/-;SEPP1} mice were increased compared with Sepp -/-} controls. When a Se adequate diet (0.16-0.2 mg/kg) was fed to the mice, liver-specific expression of SEPP1 rescued the neurological defects of Sepp -/-} mice and rendered Sepp -/-} males fertile. When fed a low-Se diet (0.06 mg/kg), 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 Se supporting the kidney, testis, and brain. Nevertheless, local Sepp expression is required to maintain Se content in Se-privileged tissues such as brain and testis during dietary Se restriction.
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