Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice

Abstract

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.

Selenoproteins: Molecular Pathways and Physiological Roles

“…Consistent with the very low Se concentrations in brain and testis, SelP knockout mice fed normal or low Se diets developed severe neurological problems and male infertility (142,308). However, tissue-specific expression of SelP in the liver of SelP Ϫ/Ϫ mice restored Se transport and prevented infertility and neurological phenotypes (295). The fact that the largest decrease in Se levels was seen in the brain and testes of SelP knockout mice indicates that SelP has a more direct role in delivering Se to these tissues.…”

Influence of ovarian stage on transcript profiles in fathead minnow (Pimephales promelas) ovary tissue

“…For example, sepp1a, the gene with the largest fold change observed in the present study, codes for a protein thought to function primarily in selenium distribution which has been reported to carry up to approximately one third of plasma selenium in humans (Akesson et al, 1994;Renko et al, 2008). Deficiency of sepp1a has been linked to impaired spermatogenesis and infertility in male mammals (e.g., Renko et al, 2008). While a similar linkage has not been established for ovary, selenium has been reported to modulate granulosa cell proliferation and estradiol production (Basini and Tamanini, 2000).…”

Distribution and Dynamic Pathway of Selenium Species in Selenium-deficient Mice Injected with 82Se-enriched Selenite

“…However, this reduction of endogenous 82 Se in the testis and epididymis was relatively small compared with that of other organs. Since Se plays an important role in sperm production, 3 we assume that some metabolic pathways work to maintain the Se concentration. As shown in Fig.…”

“…3 Se deficiency induces arterial sclerosis, 4 cardiac myopathy, 5 and infectious disease. 6 On the other hand, Se is known to be a highly toxic element, and Se excess leads to hair and nail loss as well as brittleness, gastrointestinal problem, and nervous system abnormalities.…”