The thyroid hormone receptor-beta agonist GC-1 induces cell proliferation in rat liver and pancreas.
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 TRbeta 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 mug/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 TRbeta-selective agonist GC-1 is a strong mitogen for hepatocytes and pancreatic acinar cells. Furthermore, they suggest that the TRbeta receptor is the mediator for the mitogenic activity of thyroid hormone and other thyromimetics.
Columbano
Amedeo
A
Department of Toxicology, Oncology, and Molecular Pathology Unit, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy. columbano@unica.it
Pibiri
Monica
M
Deidda
Manuela
M
Cossu
Costanza
C
Scanlan
Thomas S
TS
Chiellini
Grazia
G
Muntoni
Sandro
S
Ledda-Columbano
Giovanna M
GM
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D022781:Hepatocytes / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*; D013963:Thyroid Hormones / Q000378:metabolism
D000085:Acetates; C413355:GC 1 compound; D008055:Lipids; D010636:Phenols; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones