RESUMEN
Thyroid hormone (TH) homeostasis depends on peripheral activation and inactivation of iodothyronines by selenoenzymes of the deiodinase (Dio) family. We genetically inactivated hepatic selenoenzyme expression, including Dio1, in order to determine the contribution of hepatic Dio to circulating TH levels. Serum levels of TSH, total T(4), and total T(3) were not different from controls. We measured Dio1 and Dio2 in kidney, skeletal muscle, heart, brown adipose tissue, and brain, but did not find compensatory up-regulation in these tissues. Finally, we determined expression in the liver of the following T(3) target genes: Spot14, alpha-glycerophosphate dehydrogenase (alphaGPD), and malic enzyme (ME). On the transcript level, both Spot14 and alphaGPD were reduced in Dio-deficient liver to about 60-70% of controls. However, mRNA and activity of ME were significantly increased in the same mice. Together, our results indicate that hepatic Dio1 activity is not absolutely required to sustain the euthyroid state in mice.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Yoduro Peroxidasa/metabolismo , Hígado/enzimología , Hormonas Tiroideas/sangre , Factores de Transcripción/metabolismo , Animales , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Glicerolfosfato Deshidrogenasa/metabolismo , Yoduro Peroxidasa/sangre , Malato Deshidrogenasa/metabolismo , Ratones , Proteínas Nucleares/metabolismo , ARN Mensajero/metabolismo , Tirotropina/sangre , Distribución Tisular , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Transcripción GenéticaRESUMEN
Liver-specific inactivation of Trsp, the gene for selenocysteine tRNA, removes SePP (selenoprotein P) from plasma, causing serum selenium levels to fall from 298 microg/l to 50 microg/l and kidney selenium to decrease to 36% of wild-type levels. Likewise, glutathione peroxidase activities decreased in plasma and kidney to 43% and 18% respectively of wild-type levels. This agrees nicely with data from SePP knockout mice, supporting a selenium transport role for hepatically expressed SePP. However, brain selenium levels remain unaffected and neurological defects do not occur in the liver-specific Trsp knockout mice, while SePP knockout mice suffer from neurological defects. This indicates that a transport function in plasma is exerted by hepatically derived SePP, while in brain SePP fulfils a second, hitherto unexpected, essential role.