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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\u03b1 expression. However, whether TSH can influence HNF-4\u03b1 phosphorylation is unclear. Here, we discovered that TSH can increase HNF-4\u03b1 phosphorylation and modulate its subcellularlocalization. When HepG2 cells were treated with TSH, the phosphorylation of HNF-4\u03b1 increased and its nuclear localization was interrupted. Cytoplasmic HNF-4\u03b1 increased, while nuclear HNF-4\u03b1 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\u03b1 was disrupted. When <jats:italic>Tshr<\/jats:italic> was silenced in mice, the phosphorylation of HNF-4\u03b1 decreased and cytoplasmic HNF-4\u03b1 decreased while nuclear HNF-4\u03b1 increased. In conclusion, our study revealed a novel mechanism by which TSH regulated the hepatic HNF-4\u03b1 subcellular localization, suggesting the possibility that one of the effects of TSH is to reduce the expression of HNF-4\u03b1 target genes.<\/jats:p>","DOI":"10.1038\/srep13409","type":"journal-article","created":{"date-parts":[[2015,8,25]],"date-time":"2015-08-25T09:26:21Z","timestamp":1440494781000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Thyroid-Stimulating Hormone Increases HNF-4\u03b1 Phosphorylation via cAMP\/PKA Pathway in the Liver"],"prefix":"10.1038","volume":"5","author":[{"given":"Yongfeng","family":"Song","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongmei","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yejun","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanjia","family":"Xing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiajun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,8,25]]},"reference":[{"key":"BFsrep13409_CR1","doi-asserted-by":"publisher","first-page":"2293","DOI":"10.1101\/gad.390906","volume":"20","author":"I Kyrmizi","year":"2006","unstructured":"Kyrmizi, I. et al. 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