Thyroid-Stimulating Hormone Increases HNF-4? Phosphorylation via cAMP/PKA Pathway in the Liver.

ABSTRACT: Hepatocyte nuclear factor-4 alpha (HNF-4?) is an orphan nuclear receptor with important roles in hepatic metabolism. Protein phosphorylation plays a functional role in its nuclear localization, DNA binding, and transactivation. Thyroid-stimulating hormone (TSH) is a hormone produced by the anterior pituitary gland, whose direct effect on the metabolic pathway has been observed. Our previous study demonstrated that TSH significantly decreases hepatic nuclear HNF-4? expression. However, whether TSH can influence HNF-4? phosphorylation is unclear. Here, we discovered that TSH can increase HNF-4? phosphorylation and modulate its subcellularlocalization. When HepG2 cells were treated with TSH, the phosphorylation of HNF-4? increased and its nuclear localization was interrupted. Cytoplasmic HNF-4? increased, while nuclear HNF-4? decreased. When the cAMP/PKA pathway was inhibited by the PKA inhibitor H89 and the adenylate cyclase (AC) inhibitor SQ22536, the TSH-mediated phosphorylation of HNF-4? was disrupted. When Tshr was silenced in mice, the phosphorylation of HNF-4? decreased, and cytoplasmic HNF-4? decreased while nuclear HNF-4? increased. In conclusion, our study revealed a novel mechanism by which TSH regulated the hepatic HNF-4? subcellular localization, suggesting the possibility that one of the effects of TSH is to reduce the expression of HNF-4? target genes.

SUBMITTER: Song Y 

PROVIDER: S-EPMC4548215 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature