Background & Aims
Thyroid hormones elicit many cellular and metabolic effects in various organs. Most
of these actions, including mitogenesis, are mediated by the thyroid hormone 3,5,3′-triiodo-l-thyronine (T3) nuclear receptors (TRs). They are transcription factors, expressed
as different isoforms encoded by the TRα and TRβ genes. Here, experiments were performed
to determine whether (i) T3-induces hepatocyte proliferation in mouse liver and pancreas,
and, (ii) which TR isoform, is responsible for its mitogenic effect.
Methods
Cell proliferation was measured by bromodeoxyuridine (BrdU) incorporation after T3
or the TRβ agonist GC-1 in liver and pancreas of CD-1, C57BL, or TRα0/0 mice. Cell cycle-associated proteins were measured by Western blot.
Results
T3 added to the diet at a concentration of 4 mg/kg caused a striking increase in BrdU incorporation in mouse hepatocytes. Increased
BrdU incorporation was associated with enhanced protein levels of cyclin D1 and PCNA
and decreased levels of p27. Treatment with GC-1, a selective agonist of the TRβ isoform,
also induced a strong mitogenic response of mouse hepatocytes and pancreatic acinar
cells which was similar to that elicited by T3. Finally, treatment with T3 of mice
TRα0/0 induced a proliferative response in the liver and pancreas, similar to that of their
wild type counterpart.
Conclusions
These results demonstrate that T3 is a powerful inducer of cell proliferation in mouse
liver and suggest that the β-isoform is responsible for the hepatomitogenic activity
of T3. The same isoform seems to also mediate the proliferation of mouse pancreatic
acinar cells.
Abbreviations:
T3 (triiodothyronine), T4 (thyroxine), TRs (thyroid hormone receptors), TRα0/0 (thyroid hormone receptor alpha 0/0), PPAR (peroxisome proliferators-activated receptor), RAR (retinoic acid receptor), RXR (retinoid-X receptor), VDR (vitamin D receptor), CAR (constitutive androstane receptor), BrdU (bromodeoxyuridine), PCNA (proliferating cell nuclear antigen), wt (wild type)Keywords
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Article info
Publication history
Published online: July 05, 2010
Accepted:
April 19,
2010
Received in revised form:
March 29,
2010
Received:
December 24,
2009
Identification
Copyright
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
