Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver
Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver
复制标题
促甲状腺激素通过肝脏中 AMP 激活的蛋白激酶降低 HMG-CoA 还原酶的磷酸化
DOI：
10.1194/jlr.m047654
复制
发表时间：
2015-05-01
影响因子：
6.5
通讯作者：
Zhao, Jiajun
中科院分区：
文献类型：
--
作者：
Zhang, Xiujuan;Song, Yongfeng;Zhao, Jiajun
胆固醇稳态是通过调节HMG-CoA还原酶（HMGCR）严格调节的，HMGCR是胆固醇合成的限速酶。HMGCR的磷酸化使其失活，去磷酸化使其激活。amp活化蛋白激酶（AMPK）是磷酸化该酶的主要激酶。我们前期研究发现，促甲状腺激素（TSH）增加了肝细胞HMGCR的表达，但TSH是否影响肝脏HMGCR与AMPK相关的磷酸化尚不清楚。我们用牛TSH （bTSH）处理小鼠原代肝细胞和HepG2细胞，用或不加组成型活性(CA)-AMPK质粒或蛋白激酶A抑制剂（H89），建立TSH受体（Tshr）KO小鼠模型。检测p-HMGCR、p-AMPK及相关分子表达。bTSH刺激后，肝细胞中p-HMGCR/HMGCR和p-AMPK/AMPK的比值呈剂量依赖性下降。当CA-AMPK质粒或H89处理细胞时，上述变化完全相反。Tshr-KO小鼠肝脏p-HMGCR/HMGCR和p-AMPK/AMPK比值较野生型小鼠明显升高。与此同时，AMPK的下游靶分子乙酰辅酶a羧化酶的磷酸化也在增加。以上结果提示，TSH可通过AMPK调控HMGCR的磷酸化，这为肝脏中TSH的直接作用建立了高胆固醇血症的潜在机制。
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.