Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity
Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity
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促甲状腺素通过上调 SREBP-1c 活性来增加肝甘油三酯含量。
DOI：
10.1016/j.jhep.2014.06.037
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发表时间：
2014-12-01
影响因子：
25.7
通讯作者：
Zhao, Jiajun
中科院分区：
文献类型：
--
作者：
Yan, Fang;Wang, Qi;Zhao, Jiajun
背景与目的：非酒精性脂肪性肝病（NAFLD）的标志是肝细胞内甘油三酯积累增加。NAFLD的患病率随着促甲状腺激素（TSH）水平的增加而稳步增加。然而，其潜在的机制在很大程度上是未知的。方法：采用TSH受体（TSH receptor，TSHR）介导的促甲状腺激素（TSH）对Tshr（-/-）小鼠（补充甲状腺素）肝脏甘油三酯含量的影响。在喂食高脂肪或正常饲料的Tshr（-/-）和Tshr（+/+）小鼠以及Srebp-1c（-/-）和Tshr（-/-）Srebp-1c（-/-）小鼠中分析肝脏脂肪变性和甘油三酯含量。结果：与同窝对照组相比，高脂饮食诱导Tshr（-/-）小鼠肝脏脂肪变性程度相对较低。即使在普通饲料下，Tshr（-/-）小鼠的肝脏甘油三酯含量也降低。促甲状腺激素对体外培养肝细胞内甘油三酯含量有浓度和时间依赖性影响。SREBP-1c是一种参与甘油三酯代谢和NAFLD发病机制的关键调节因子，其活性在Tshr（-/-）小鼠中显著降低。在Tshr（-/-）Srebp-1c（-/-）小鼠中，肝脏甘油三酯含量与Tshr（+/+）Srebp-1c（-/-）小鼠相比无显著差异。当给小鼠注射forskolin（cAMP激活剂）、H89（PKA抑制剂）或AICAR（AMPK激活剂）或HeG 2细胞接受MK 886（PPAR α抑制剂）时，甘油三酯含量以依赖于SREBP-1c活性的方式呈现。TSH诱导的肝脏甘油三酯积累的机制，涉及TSH，通过其受体TSHR，触发肝SREBP-1c活性通过cAMP/PKA/PPAR α通路与减少AMPK，这进一步增加了与脂肪生成相关的基因的表达。结论：TSH增加肝脏甘油三酯含量，表明TSH在NAFLD的发病机制中的重要作用。(C)2014年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Hallmarks of non-alcoholic fatty liver disease (NAFLD) are increased triglyceride accumulation within hepatocytes. The prevalence of NAFLD increases steadily with increasing thyrotropin (TSH) levels. However, the underlying mechanisms are largely unknown. Here, we focused on exploring the effect and mechanism of TSH on the hepatic triglyceride content.Methods: As the function of TSH is mediated through the TSH receptor (TSHR), Tshr(-/-) mice (supplemented with thyroxine) were used. Liver steatosis and triglyceride content were analysed in Tshr(-/-) and Tshr(+/+) mice fed a high-fat or normal chow diet, as well as in Srebp-1c(-/-) and Tshr(-/-) Srebp-1c(-/-) mice. The expression levels of proteins and genes involved in liver triglyceride metabolism was measured.Results: Compared with control littermates, the high-fat diet induced a relatively low degree of liver steatosis in Tshr(-/-) mice. Even under chow diet, hepatic triglyceride content was decreased in Tshr(-/-) mice. TSH caused concentration-and time-dependent effects on intracellular triglyceride contents in hepatocytes in vitro. The activity of SREBP-1c, a key regulator involved in triglyceride metabolism and in the pathogenesis of NAFLD, was significantly lower in Tshr(-/-) mice. In Tshr(-/-) Srebp-1c(-/-) mice, the liver triglyceride content showed no significant difference compared with Tshr(+/+) Srebp-1c(-/-) mice. When mice were injected with forskolin (cAMP activator), H89 (inhibitor of PKA) or AICAR (AMPK activator), or HeG2 cells received MK886 (PPAR alpha inhibitor), triglyceride contents presented in a manner dependent on SREBP-1c activity. The mechanism, underlying TSH-induced liver triglyceride accumulation, involved that TSH, through its receptor TSHR, triggered hepatic SREBP-1c activity via the cAMP/PKA/PPAR alpha pathway associated with decreased AMPK, which further increased the expression of genes associated with lipogenesis.Conclusions: TSH increased the hepatic triglyceride content, indicating an essential role for TSH in the pathogenesis of NAFLD. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.