Repair-Related Activation of Hedgehog Signaling in Stromal Cells Promotes Intrahepatic Hypothyroidism
Repair-Related Activation of Hedgehog Signaling in Stromal Cells Promotes Intrahepatic Hypothyroidism
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DOI：
10.1210/en.2014-1302
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发表时间：
2014-11-01
期刊：
影响因子：
4.8
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Bohinc, Brittany N.;Michelotti, Gregory;Diehl, Anna Mae
甲状腺激素（TH）对组织修复很重要，因为它调节细胞分化。肝内TH活性受血清TH水平和肝脱碘酶控制。TH底物（T-4）被脱碘酶1（D1）转化为活性激素（T-3），但被脱碘酶3（D3）转化为非活性激素（rT（3））。虽然已知D1和D3的相对表达在肝损伤期间发生变化，但涉及的细胞类型和信号传导机制尚不清楚。我们评估了肝脱碘酶的变化是由基质细胞中Hedgehog通路的修复相关激活引起的这一假设。我们定位脱碘酶的表达，评估损伤过程中的变化，并确定如何有针对性地操纵基质细胞中的Hedgehog信号影响啮齿动物的肝脱碘酶表达，TH含量和TH作用。还研究了患有慢性肝病的人。在健康肝脏中，肝细胞强烈表达D1，基质细胞弱表达D3。在损伤过程中，肝细胞表达的D1下降，而基质表达的D3增加，特别是在肌成纤维细胞。在肌成纤维细胞中干扰Hedgehog信号使脱碘酶表达正常化。修复相关的变化，脱碘酶伴随着减少肝脏TH含量和TH调节基因表达。在患者中，这反映在血清r（T）3升高。此外，游离T-3/rT（3）和游离T-4/rT（3）比值的降低可区分晚期和轻度纤维化，即使在血清TSH和游离T-4水平相似的个体中也是如此。总之，Hedgehog依赖的肝基质细胞的变化驱动肝脱碘酶表达的修复相关变化，促进肝内甲状腺功能减退，从而限制暴露于T-3，细胞分化的重要因素。
Thyroid hormone (TH) is important for tissue repair because it regulates cellular differentiation. Intrahepatic TH activity is controlled by both serum TH levels and hepatic deiodinases. TH substrate (T-4) is converted into active hormone (T-3) by deiodinase 1 (D1) but into inactive hormone (rT(3)) by deiodinase 3 (D3). Although the relative expressions of D1 and D3 are known to change during liver injury, the cell types and signaling mechanisms involved are unclear. We evaluated the hypothesis that changes in hepatic deiodinases result from repair-related activation of the Hedgehog pathway in stromal cells. We localized deiodinase expression, assessed changes during injury, and determined how targeted manipulation of Hedgehog signaling in stromal cells impacted hepatic deiodinase expression, TH content, and TH action in rodents. Humans with chronic liver disease were also studied. In healthy liver, hepatocytes strongly expressed D1 and stromal cells weakly expressed D3. During injury, hepatocyte expression of D1 decreased, whereas stromal expression of D3 increased, particularly in myofibroblasts. Conditionally disrupting Hedgehog signaling in myofibroblasts normalized deiodinase expression. Repair-related changes in deiodinases were accompanied by reduced hepatic TH content and TH-regulated gene expression. In patients, this was reflected by increased serum r(T)3. Moreover, the decreases in the free T-3 to rT(3) and free T-4 to rT(3) ratios distinguished advanced from mild fibrosis, even in individuals with similar serum levels of TSH and free T-4. In conclusion, the Hedgehog-dependent changes in liver stromal cells drive repair-related changes in hepatic deiodinase expression that promote intrahepatic hypothyroidism, thereby limiting exposure to T-3, an important factor for cellular differentiation.