title: Thyroid-Stimulating Hormone Increases HNF-4α Phosphorylation via cAMP/PKA Pathway in the Liver.
abstract: Hepatocyte nuclear factor-4 alpha (HNF-4α) 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-4α expression. However, whether TSH can influence HNF-4α phosphorylation is unclear. Here, we discovered that TSH can increase HNF-4α phosphorylation and modulate its subcellularlocalization. When HepG2 cells were treated with TSH, the phosphorylation of HNF-4α increased and its nuclear localization was interrupted. Cytoplasmic HNF-4α increased, while nuclear HNF-4α 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-4α was disrupted. When Tshr was silenced in mice, the phosphorylation of HNF-4α decreased, and cytoplasmic HNF-4α decreased while nuclear HNF-4α increased. In conclusion, our study revealed a novel mechanism by which TSH regulated the hepatic HNF-4α subcellular localization, suggesting the possibility that one of the effects of TSH is to reduce the expression of HNF-4α target genes.
authors: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors: Yongfeng
authors: Y
authors: Song
authors: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors: Dongmei
authors: D
authors: Zheng
authors: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors: Meng
authors: M
authors: Zhao
authors: Department of pathology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors: Yejun
authors: Y
authors: Qin
authors: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors: Tingting
authors: T
authors: Wang
authors: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors: Wanjia
authors: W
authors: Xing
authors: Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors: Ling
authors: L
authors: Gao
authors: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors: Jiajun
authors: J
authors: Zhao
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013972:Thyrotropin / Q000008:administration & dosage*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D013972:Thyrotropin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases