Specific excision of the selenocysteine tRNA[Ser]Sec (Trsp) gene in mouse liver demonstrates an essential role of selenoproteins in liver function.
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.
Carlson
Bradley A
BA
Section on the Molecular Biology of Selenium, Basic Research Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland, 20892, USA.
Novoselov
Sergey V
SV
Kumaraswamy
Easwari
E
Lee
Byeong Jae
BJ
Anver
Miriam R
MR
Gladyshev
Vadim N
VN
Hatfield
Dolph L
DL
D000418:Albumins / Q000235:genetics; D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D005982:Glutathione Transferase / Q000032:analysis; D006720:Homozygote; D019426:Integrases / Q000235:genetics; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D014176:Protein Biosynthesis; D011506:Proteins / Q000032:analysis / Q000502:physiology*; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics* / Q000502:physiology; D012643:Selenium / Q000032:analysis; D051149:Selenoprotein P; D051140:Selenoproteins
D000418:Albumins; D011506:Proteins; D012346:RNA, Transfer, Amino Acyl; D051149:Selenoprotein P; D051140:Selenoproteins; C112705:selenocysteinyl-tRNA; D005982:Glutathione Transferase; D019426:Integrases; D012643:Selenium