Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver.
Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver.
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DOI：
10.1530/joe-14-0440
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发表时间：
2015-03
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影响因子：
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通讯作者：
Aijun Zhang;D. Sieglaff;J. P. York;J. Suh;S. Ayers;Glenn E. Winnier;A. Kharitonenkov;C. Pin;Pumin Zhang;P. Webb;Xuefeng Xia
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作者：
Aijun Zhang;D. Sieglaff;J. P. York;J. Suh;S. Ayers;Glenn E. Winnier;A. Kharitonenkov;C. Pin;Pumin Zhang;P. Webb;Xuefeng Xia
甲状腺激素（TH）通过特异性受体（TR）（条件转录因子）诱导成纤维细胞生长因子21（FGF 21），FGF 21是一种肽激素，通常由禁食诱导，通过局部肝脏和全身内分泌效应影响脂质和碳水化合物代谢。虽然TH和FGF 21在施用时显示重叠作用，包括降低血清脂质，但根据目前的模型，这些激素在体内独立起作用。在这项研究中，我们研究了TH调控FGF 21表达的机制，并测试了FGF 21是诱导肝脏TH反应基因所需的可能性。我们证实，活性TH（三碘甲状腺原氨酸（T3））和TRβ选择性拟甲状腺素GC 1增加小鼠肝脏中FGF 21的转录和肽水平，这种作用需要TRβ。T3还诱导培养的肝细胞中的FGF 21，并且该作用涉及TRβ1的直接作用，TR β 1结合FGF 21的内含子2内的TRE。WT和Fgf 21敲除小鼠的基因表达谱非常相似，表明FGF 21对于大多数肝脏T3基因应答是不稳定的。一小部分基因在没有FGF 21的情况下表现出减弱的T3应答。然而，其中大多数并不明显直接参与T3依赖性肝脏代谢过程。与这些结果一致，在Fgf 21（-/-）背景下维持对血清胆固醇的T3依赖性作用，并且我们观察到Fgf 21敲除背景对血清甘油三酯和葡萄糖没有作用。我们的研究结果表明，T3调节基因参与经典的肝脏代谢反应独立的FGF 21。
Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While TH and FGF21 display overlapping actions when administered, including reductions in serum lipids, according to the current models these hormones act independently in vivo. In this study, we examined mechanisms of regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRβ-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WT and Fgf21-knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in the Fgf21(-/-) background and we observe no effect of the Fgf21-knockout background on serum triglycerides and glucose. Our findings indicate that T3 regulates the genes involved in classical hepatic metabolic responses independently of FGF21.