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J Hepatol. 2010 Oct;53(4):686-92. doi: 10.1016/j.jhep.2010.04.028. Epub 2010 Jul 1.

TRbeta is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells.

Author information

1
Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy.

Abstract

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 TRalpha and TRbeta 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 TRbeta agonist GC-1 in liver and pancreas of CD-1, C57BL, or TRalpha(0/0) 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 TRbeta 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 TRalpha(0/0) 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 beta-isoform is responsible for the hepatomitogenic activity of T3. The same isoform seems to also mediate the proliferation of mouse pancreatic acinar cells.

PMID:
20638743
DOI:
10.1016/j.jhep.2010.04.028
[Indexed for MEDLINE]

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