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

Biochem Biophys Res Commun. 2017 Nov 25;493(3):1304-1310. doi: 10.1016/j.bbrc.2017.09.169. Epub 2017 Sep 30.

Abstract

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.

Keywords: Akt; Fibroblasts; Fibronectin; HIF-1; Hepatoma cells; T3.

MeSH terms

  • Androstadienes / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibronectins / genetics
  • Fibronectins / metabolism*
  • Hep G2 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Triiodothyronine / metabolism*
  • Triiodothyronine / pharmacology
  • Wortmannin

Substances

  • Androstadienes
  • Fibronectins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Triiodothyronine
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Wortmannin