Videla Luis A, Vargas Romina, Riquelme Barbara, Fernández Javier, Fernández Virginia
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Exp Clin Endocrinol Diabetes. 2018 Mar;126(3):182-186. doi: 10.1055/s-0043-115533. Epub 2017 Sep 11.
Thyroid hormone (3,3',5-triiodothyronine, T) accelerates energy metabolism in the liver through mechanisms involving upregulation of AMP-activated protein kinase (AMPK). This study aims to assess the influence of T on the expression of the scaffold proteins β-Klotho, fibroblast growth factor receptor substrate 2α (FRS2α), and Sestrin2 in relation to FGF21-AMPK signaling. Male Sprague-Dawley rats were given 0.1 mg T/kg or hormone vehicle (controls) and studies were done 24 h after treatment. These include measurements of the mRNA expression (qPCR) of hepatic β-Klotho, FGF21, FGF21 receptor-1 (FGFR1), extracellular-signal-regulated kinase 1/2 (ERK1/2), FRS2α, ribosomal S6 kinase-1 (RSK1), liver kinase B1 (LKB1), AMPK, and Sestrin2. Also, protein levels of FGF21, FGFR1 (ELISA), and ERK1/2 (Western blot) were measured. T elicited a calorigenic response with higher hepatic mRNA expression of β-Klotho, FRS2α, and FGF21, increased serum FGF21, without changes in liver FGFR1 mRNA and its plasma levels. In addition, T enhanced ERK1/2 phosphorylation and the mRNA expression of ERK1/2, RSK1, LKB1, AMPK, and Sestrin2. T administration enhances liver FGF21-AMPK signaling involving upregulation of the scaffold proteins β-Klotho, FRS2α, and Sestrin2. β-Klotho and FRS2 induction favours the operation of the FGF21-FGFR1-β-Klotho complex as evidenced by the enhancement in ERK1/2 phosphorylation, whereas that of Sestrin2 recruits LKB1 to achieved AMPK activation, thus supporting a higher energy expenditure condition that may be desirable in some metabolic disorders.
甲状腺激素（3,3',5-三碘甲状腺原氨酸，T₃）通过涉及上调AMP激活的蛋白激酶（AMPK）的机制加速肝脏中的能量代谢。本研究旨在评估T₃对支架蛋白β-klotho、成纤维细胞生长因子受体底物2α（FRS2α）和Sestrin2表达的影响，以及与FGF21-AMPK信号传导的关系。给雄性Sprague-Dawley大鼠注射0.1mg T₃/kg或激素载体（对照组），并在治疗后24小时进行研究。这些研究包括测量肝脏β-klotho、FGF21、FGF21受体-1（FGFR1）、细胞外信号调节激酶1/2（ERK1/2）、FRS2α、核糖体S6激酶-1（RSK1）、肝脏激酶B1（LKB1）、AMPK和Sestrin2的mRNA表达（qPCR）。此外，还测量了FGF21、FGFR1（ELISA）和ERK1/2（蛋白质印迹法）的蛋白质水平。T₃引发了产热反应，肝脏中β-klotho、FRS2α和FGF21的mRNA表达升高，血清FGF21增加，而肝脏FGFR1 mRNA及其血浆水平没有变化。此外，T₃增强了ERK1/2磷酸化以及ERK1/2、RSK1、LKB1、AMPK和Sestrin2的mRNA表达。给予T₃可增强肝脏FGF21-AMPK信号传导，包括上调支架蛋白β-klotho、FRS2α和Sestrin2。β-klotho和FRS2的诱导有利于FGF21-FGFR1-β-klotho复合物的运作，这通过ERK1/2磷酸化的增强得到证明，而Sestrin2的诱导则招募LKB1以实现AMPK激活，从而支持在某些代谢紊乱中可能需要的更高能量消耗状态。
