Thyroid hormone regulates fibronectin expression through the activation of the hypoxia inducible factor 1

• Published in: Biochemical and biophysical research communications 2017-11, Vol.493 (3), p.1304-1310
• Main Authors: Taglieri, Ludovica, Nardo, Tiziana, Vicinanza, Roberto, Ross, Jaime M., Scarpa, Susanna, Coppotelli, Giuseppe
• Format: Article
• Language: English
• Subjects: Akt; Androstadienes - pharmacology; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibronectin; Fibronectins - genetics; Fibronectins - metabolism; Hep G2 Cells; Hepatoma cells; HIF-1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medicin och hälsovetenskap; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Triiodothyronine - metabolism; Triiodothyronine - pharmacology; Wortmannin
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2017.09.169

Thyroid hormones regulate gene expression via both canonical and non-canonical signaling. Hyperthyroidism is associated with elevated plasma levels of fibronectin (FN): in this study we elucidate the molecular mechanism through which triiodothyronine (T3) regulates FN and demonstrate that T3 induces FN expression via a non-canonical pathway by activating hypoxia-inducible factor-1 (HIF-1). We found that T3 treatment increased cellular and secreted FN in human hepatoma cells (HepG2) and human dermal fibroblasts (HF) via the PI3K/Akt/HIF-1 pathway. The inhibition of either Akt phosphorylation with wortmannin or HIF-1 with YC1 in both cell types prevented HIF-1α synthesis and FN positive regulation upon T3 treatment. We showed that HIF-1α overexpression per se was sufficient to up-regulate FN in both cell lines as demonstrated by the transient transfection of both the constitutively active and wild-type forms of HIF-1α. Our data demonstrate the involvement of the PI3K/Akt/HIF-1 pathway in mediating T3 induced FN up-regulation. •Thyroid hormone induces HIF-1α synthesis via PI3K/AKT signaling pathway.•HIF-1α increases fibronectin expression and secretion in hepatoma cells and fibroblasts.•PI3K/Akt/HIF-1 is required for T3 induction of fibronectin synthesis and release.