title: Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver.
abstract: Cholesterol homeostasis is strictly regulated through the modulation of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of cholesterol synthesis. Phosphorylation of HMGCR inactivates it and dephosphorylation activates it. AMP-activated protein kinase (AMPK) is the major kinase phosphorylating the enzyme. Our previous study found that thyroid-stimulating hormone (TSH) increased the hepatocytic HMGCR expression, but it was still unclear whether TSH affected hepatic HMGCR phosphorylation associated with AMPK. We used bovine TSH (bTSH) to treat the primary mouse hepatocytes and HepG2 cells with or without constitutively active (CA)-AMPK plasmid or protein kinase A inhibitor (H89), and set up the TSH receptor (Tshr)-KO mouse models. The p-HMGCR, p-AMPK, and related molecular expression were tested. The ratios of p-HMGCR/HMGCR and p-AMPK/AMPK decreased in the hepatocytes in a dose-dependent manner following bTSH stimulation. The changes above were inversed when the cells were treated with CA-AMPK plasmid or H89. In Tshr-KO mice, the ratios of liver p-HMGCR/HMGCR and p-AMPK/AMPK were increased relative to the littermate wild-type mice. Consistently, the phosphorylation of acetyl-CoA carboxylase, a downstream target molecule of AMPK, increased. All results suggested that TSH could regulate the phosphorylation of HMGCR via AMPK, which established a potential mechanism for hypercholesterolemia involved in a direct action of the TSH in the liver.
authors.affiliation: Departments of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Feng
authors.affiliation: Departments of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Ninth People'sHospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200011, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Departments of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Departments of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Departments of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013449:Sulfonamides / Q000494:pharmacology; D013972:Thyrotropin / Q000502:physiology*
chemical_list: D007546:Isoquinolines; D013449:Sulfonamides; D013972:Thyrotropin; D006903:Hydroxymethylglutaryl CoA Reductases; D017868:Cyclic AMP-Dependent Protein Kinases; D000263:Adenylate Kinase; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: adenosine 5′-monophosphate-activated protein kinase; cholesterol; hydroxy-methylglutaryl coenzyme A reductase