Endocrine Abstracts

Fibrosis represents a major health concern and presently has no successful treatment. Chronic liver fibrosis leads to portal hypertension, cirrhosis, hepatocellular carcinoma and liver failure. Transforming growth factor β (TGFβ), the main profibrogenic factor, mediates its actions mainly through activation of Smad transcription factors. We have previously observed a cross-talk between the thyroid hormone receptors (TRs) and the TGFβ pathway by which the thyroid hormone-bound TRs can antagonize TGFβ-mediated responses. Here, we demonstrate the functional importance of this antagonism in vivo using a mouse model of hepatic fibrosis induced by CCl4, a widely used hepatotoxic agent. In normal mice, acute treatment (48 h) with CCl4 caused significant necrosis with nuclei loss of hepatocytes surrounding centrilobular veins, while this was not observed in hyperthyroid mice. Concomitantly, induction of Smad2 phosphorylation in response to CCl4 was markedly blunted in the hyperthyroid animals, showing that the thyroid hormones reduce activation of the TGFβ pathway in vivo. Moreover, after chronic exposure to CCl4, the hyperthyroid animals developed a less severe liver fibrosis, with less Collagen 1 deposition and significantly reduced expression of α-SMA, the main marker of myofibroblast activation. The mRNA levels of Col1a1, Col1a2 and α-Sma in response to CCl4 were also lower in the hyperthyroid mice. Furthermore, fibrosis appeared spontaneously in livers of 18-month-old mice in which TRs have been genetically ablated, thus implicating these receptors as physiological negative regulators of the fibrotic response in vivo in this organ. These finding define a novel function of the thyroid hormone receptors, and suggest that development of novel TR ligands capable of disrupting TGFβ/SMAD activity could constitute a novel therapeutic approach to block the progression of fibrotic diseases.

Disclosure: BFU2011-28058 from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET, from the Comunidad de Madrid and RD12/0036/0030 from the Instituto de Salud Carlos III.