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

• Published in: Journal of hepatology 2010-10, Vol.53 (4), p.686-692
• Main Authors: Kowalik, Marta A, Perra, Andrea, Pibiri, Monica, Cocco, Maria T, Samarut, Jacques, Plateroti, Michelina, Ledda-Columbano, Giovanna M, Columbano, Amedeo
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Computer Science; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; GC-1; Life Sciences; Liver; Medical sciences; Pancreas; Thyroid hormone; Thyromimetics
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2010.04.028

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.