Specific Excision of the Selenocysteine tRNA[Ser]Sec (Trsp) Gene in Mouse Liver Demonstrates an Essential Role of Selenoproteins in Liver Function

Abstract

Selenium is essential in mammalian embryonic development. However, in adults, selenoprotein levels in several organs including liver can be substantially reduced by selenium deficiency without any apparent change in phenotype. To address the role of selenoproteins in liver function, mice homozygous for a floxed allele encoding the selenocysteine (Sec) tRNA[Ser]Sec gene were crossed with transgenic mice carrying the Cre recombinase under the control of the albumin promoter that expresses the recombinase specifically in liver. Recombination was nearly complete in mice 3 weeks of age, whereas liver selenoprotein synthesis was virtually absent, which correlated with the loss of Sec tRNA[Ser]Sec and activities of major selenoproteins. Total liver selenium was dramatically decreased, whereas levels of low molecular weight selenocompounds were little affected. Plasma selenoprotein P levels were reduced by about 75%, suggesting that selenoprotein P is primarily exported from the liver. Glutathione S-transferase levels were elevated in the selenoprotein-deficient liver, suggesting a compensatory activation of this detoxification program. Mice appeared normal until about 24 h before death. Most animals died between 1 and 3 months of age. Death appeared to be due to severe hepatocellular degeneration and necrosis with concomitant necrosis of peritoneal and retroperitoneal fat. These studies revealed an essential role of selenoproteins in liver function.

Selenoprotein deficiency and high levels of selenium compounds can effectively inhibit hepatocarcinogenesis in transgenic mice

“…Previous studies reported elevated expression of detoxification and repair enzymes in Se-deficient mouse livers (Reiter and Wendel, 1984;Carlson et al, 2004), as well as in cells treated with high levels of Se (El-Bayoumy and Sinha, 2004;Zhao et al, 2004). In addition, Se deficiency had a protective effect against acetaminophen and aflatoxin injuries in rat livers, presumably due to stimulation of GSH synthesis and induction of expression of detoxification enzymes (Burk and Lane, 1983;Hill and Burk, 1984).…”

Metformin Suppresses Expression of the Selenoprotein P Gene via an AMP-activated Kinase (AMPK)/FoxO3a Pathway in H4IIEC3 Hepatocytes

“…Cells were cultured in Dulbecco's modified Eagle's medium (DMEM; Invitrogen) and supplemented with 10% fetal bovine serum (Invitrogen), 2 mmol/liter L-glutamine (WaKo Pure Chemical Industries, Ltd.), 100 units/ml penicillin, and 0.1 mg/ml streptomycin (WaKo Pure Chemical Industries, Ltd.). The cells were cultured at 37°C in a humidified atmosphere containing 5% CO 2 .…”

Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells

“…Selenoprotein P (SeP, encoded by the SEPP1 gene in human and the Sepp1 gene in mice) is a secretory protein produced primarily in the liver [12,13]. It contains 10 selenocysteine residues and functions as a selenium supply protein [14].…”