Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse.
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.
Zavacki
Ann Marie
AM
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
Ying
Hao
H
Christoffolete
Marcelo A
MA
Aerts
Goele
G
So
Edward
E
Harney
John W
JW
Cheng
Sheue-Yann
SY
Larsen
P Reed
PR
Bianco
Antonio C
AC
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
D015415:Biomarkers; D012333:RNA, Messenger; D014284:Triiodothyronine; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase; D013974:Thyroxine