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The Thyroid Hormone Receptor-ß Agonist GC-1 Induces Cell Proliferation in Rat Liver and Pancreas

Department of Toxicology, Oncology and Molecular Pathology Unit (A.C., M.P., M.D., C.C., S.M., G.M.L.-C.), University of Cagliari, 09124 Cagliari, Italy; Department of Pharmaceutical Chemistry (T.S.S.), University of California-San Francisco, San Francisco, California 94143; and Dipartimento di Scienze dell’Uomo e dell’Ambiente (G.C.), University of Pisa, Pisa 56126, Italy

Address all correspondence and requests for reprints to: Dr. A. Columbano, Dipartimento di Tossicologia, Sezione di Oncologia e Patologia Molecolare, Via Porcell 4, 09124 Cagliari, Italy. E-mail: columbano{at}unica.it.

Thyroid hormones regulate cell growth, cell differentiation, and metabolic functions via interaction with the thyroid hormone nuclear receptors (TRs). Recently, a small class of halogen-free high-affinity thyroid hormone agonists has been developed that are highly selective for the TRß subtype. Because of the selective hyperthyroidism generated by one of these agonists, GC-1, this compound has the potential to be developed as a new therapeutic agent for the treatment of a variety of metabolic disturbances, including lipid disorders and obesity; thus, it becomes important to determine whether GC-1 has other unknown effects on potential target organs. The purpose of this study was to investigate the effect of GC-1 on cell proliferation in rat liver and pancreas. Rats treated with GC-1 (50 or 100 µg/100 g body weight) were killed at different time points. Hepatic and pancreatic cell proliferation was monitored by immunohistochemical determination of bromodeoxyuridine incorporation. The expression of cell cycle-related genes was analyzed by Northern and Western analysis. The results show that GC-1 strongly stimulates rat hepatocyte proliferation in the absence of tissue injury. Although GC-1-induced hepatocyte proliferation was associated with a rapid increase in cyclin D1 mRNA levels, no change in the expression of c-jun and c-fos was observed. GC-1 also induced massive pancreatic cell proliferation. The results indicate that the TRß-selective agonist GC-1 is a strong mitogen for hepatocytes and pancreatic acinar cells. Furthermore, they suggest that the TRß receptor is the mediator for the mitogenic activity of thyroid hormone and other thyromimetics.

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