Zhang Aijun, Sieglaff Douglas H, York Jean Philippe, Suh Ji Ho, Ayers Stephen D, Winnier Glenn E, Kharitonenkov Alexei, Pin Christopher, Zhang Pumin, Webb Paul, Xia Xuefeng
Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
J Endocrinol. 2015 Mar;224(3):289-301. doi: 10.1530/JOE-14-0440. Epub 2014 Dec 11.
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.
甲状腺激素（TH）通过特异性受体（TRs）发挥作用，TRs是条件性转录因子，可诱导成纤维细胞生长因子21（FGF21），FGF21是一种肽类激素，通常由禁食诱导产生，并通过局部肝脏和全身内分泌作用影响脂质和碳水化合物代谢。虽然TH和FGF21在给药时表现出重叠作用，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发挥作用。在本研究中，我们研究了TH对FGF21表达的调控机制，并测试了FGF21是否是诱导肝脏TH反应性基因所必需的。我们证实活性TH（三碘甲状腺原氨酸（T3））和TRβ选择性甲状腺模拟物GC1可增加小鼠肝脏中FGF21转录本和肽水平，且这种作用需要TRβ。T3还可在培养的肝细胞中诱导FGF21，这种作用涉及TRβ1的直接作用，TRβ1与FGF21内含子2中的甲状腺激素反应元件（TRE）结合。野生型（WT）和Fgf21基因敲除小鼠的基因表达谱非常相似，表明FGF21对于大多数肝脏T3基因反应并非必需。在缺乏FGF21的情况下，一小部分基因的T3反应减弱。然而，其中大多数基因显然并不直接参与T3依赖的肝脏代谢过程。与这些结果一致，在Fgf21（-/-）背景下，T3对血清胆固醇的依赖性作用得以维持，并且我们观察到Fgf21基因敲除背景对血清甘油三酯和葡萄糖没有影响。我们的研究结果表明，T3独立于FGF21调节参与经典肝脏代谢反应的基因。
