title: Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse.
abstract: Mice with one thyroid hormone receptor (TR) alpha-1 allele encoding a dominant negative mutant receptor (TR alpha1(PV/+)) have persistently elevated serum T3 levels (1.9-fold above normal). They also have markedly increased hepatic type 1 iodothyronine deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T3-responsive genes, such as Spot14 and mitochondrial alpha-glycerol phosphate dehydrogenase (alpha-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TR alpha1+/+). To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3. Hypothyroidism decreased hepatic D1, Spot14, and alpha-GPD mRNA to similar levels in TR alpha1+/+ and TR alpha1(PV/+) mice, whereas T3 administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and alpha-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 iodothyronine deiodinase activity was 3 times greater in the TR alpha1(PV/+) mice, and these mice had no T3-dependent induction of type 3 iodothyronine deiodinase. Thus, the marked responsiveness of hepatic D1 to T3 relative to other genes, such as Spot14 and alpha-GPD, explains the relatively large effect of the modest increase in serum T3 in the TR alpha1(PV/+) mice, and TR alpha plays a key role in T3-dependent positive and negative regulation of the deiodinases in the cerebral cortex.
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 641, Boston, Massachusetts 02115, USA. azavacki@rics.bwh.harvard.edu
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Christoffolete
authors.forename: Goele
authors.initials: G
authors.lastname: Aerts
authors.forename: Edward
authors.initials: E
authors.lastname: So
authors.forename: John W
authors.initials: JW
authors.lastname: Harney
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
mesh_terms: D000818:Animals; D015415:Biomarkers; D002540:Cerebral Cortex / Q000378:metabolism; D006579:Heterozygote; D007037:Hypothyroidism; D007453:Iodide Peroxidase / Q000096:biosynthesis* / Q000737:chemistry*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D013997:Time Factors; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D014284:Triiodothyronine; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D013974:Thyroxine