Triiodothyronine‐Induced Hepatocyte Proliferation Requires β‐Catenin

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Triiodothyronine (T3) exerts its action in inducing cell growth and differentiation by binding to their nuclear receptors. T3 is also a potent mitogen for differentiated hepatocytes that is distinct from growth factors. It was shown by immunohistochemistry that T3 administration induces cyclin D1 and expression of β‐catenin. Indeed, while T3 induced hepatocyte proliferation in wild‐type mice (WT), no proliferative response to T3 was observed in hepatocyte‐specific β‐catenin knockout mice (KO). T3 treatment of rat and mouse hepatocytes induced β‐catenin activity as assessed by TOPflash reporter assay. Furthermore, in vivo experiments demonstrate that T3 treatment does not activate the canonical Wnt signaling or disrupt E‐cadherin‐β‐catenin complex but leads to increased Ser675‐β‐catenin. As this phosphorylation is PKA‐mediated, we next treated T3‐fed mice with PKA inhibitor H89. Concomitant administration of T3 and H89 led to a significant decrease in cyclin‐D1 expression and in turn reduced T3‐mediated hepatocyte proliferation. Thus β‐catenin is essential for T3‐ mediated mitogenic response in hepatocytes and may have therapeutic implications in liver insufficiency.