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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by Liver X receptor α through a sterol regulatory element-binding protein 1c-dependent mechanism in mice
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Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by Liver X receptor α through a sterol regulatory element-binding protein 1c-dependent mechanism in mice

机译：甲状腺激素反应性SPOT 14同源物促进肝脏脂肪生成，其表达受小鼠肝脏中X受体α通过固醇调节元件结合蛋白1c依赖性机制的调节

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摘要

The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet-fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-β gene-deficient mice, but not in LXR-α or LXR-α/β double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene-deficient mice. Sequence analysis revealed four LXR response-element-like elements and one sterol regulatory element (SRE)-binding site within a -2,468 ～+1-base-pair region of the Thrsp promoter. TO901317 treatment and LXR-α overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c-induced Thrsp transcription. Conclusion: Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-α-mediated, SREBP-1c-dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD.
机译：据报道，这种蛋白是甲状腺激素反应性SPOT 14同源物（Thrsp），是培养的肝细胞中的致脂基因，暗示Thrsp在非酒精性脂肪肝疾病（NAFLD）发病机理中的重要作用。已知Thrsp表达受多种转录因子的调节，包括甲状腺激素受体，孕烷X受体和组成型雄甾烷受体。新兴的体外证据还指出，肝脏X受体（LXR）在调节肝细胞Thrsp转录中起关键作用。在本研究中，我们显示了db / db小鼠和高脂饮食喂养的小鼠（两种鼠NAFLD模型）的肝脏中Thrsp上调。肝的Thrsp过表达增加了C57Bl / 6小鼠肝脏中甘油三酸酯的积累，并增强了脂肪生成，而肝Thrsp基因沉默则减弱了db / db小鼠的脂肪肝表型。 LXR激活剂TO901317在野生型（WT）和LXR-β基因缺陷小鼠的肝脏中诱导Thrsp表达，但在LXR-α或LXR-α/β双敲除小鼠中未诱导。 TO901317处理显着增强了WT小鼠肝固醇调节元件结合蛋白1c（SREBP-1c）的表达和活性，但未能诱导SREBP-1c基因缺陷小鼠的Thrsp表达。序列分析显示，在Thrsp启动子的-2,468〜+ 1碱基对区域内有4个LXR反应元件样元件和一个固醇调节元件（SRE）结合位点。 TO901317处理和LXR-α过表达均无法诱导，而SREBP-1c的过表达则显着提高了Thrsp启动子的活性。此外，SRE位点的删除完全废除了SREBP-1c诱导的Thrsp转录。结论：Thrsp是肝脏中的一种致脂基因，由LXR激动剂通过LXR-α介导的SREBP-1c依赖性机制诱导。因此，Thrsp可能代表了NAFLD的潜在治疗靶标。

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