Wnt/β‐catenin pathway is activated by thyroid hormone and is required for its hepatomitogenic activity

Abstract

Thyroid hormones regulate cell growth, cell differentiation, and metabolic functions via their interaction with the thyroid hormone nuclear receptors (TRs). Recently, it was shown that intestinal epithelial cell proliferation is controlled by triiodothyronine (T3), and that TR‐β directly controls transcription of the β‐catenin gene. However, whether T3 has any effect on the activation of the Wnt pathway and β‐catenin in the liver, is unknown. Here we show by immunohistochemistry that livers from T3‐treated rats exhibited a strong increase in β‐catenin protein with its accumulation in the cytoplasm and an overall increase in the number of β‐catenin‐positive hepatocytes. The increased expression of β‐catenin was associated with increased glutamine synthetase, and an enhancement in nuclear accumulation of cyclin D1, both known targets of β‐catenin. Moreover, while T3 induced hepatocyte proliferation in wt mice, no proliferative response was observed in Ctnnb1−/− mice. T3 treatment also caused enhanced levels of Cyp2E1 mRNA, another gene known to be up‐regulated by β‐catenin. The increased expression of Cyp2E1 was associated with liver injury and mortality induced by a single administration of acetaminophen.ConclusionOur results indicate that T3 induces Ctnnb1 transcription and that high levels of this hormone may be responsible, through activation of β‐catenin, of increased hepatocyte proliferation and an enhanced susceptibility to drug‐induced liver injury. AIRC and PRIN, Italy.