Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations.
Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations.
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核激素受体作为生殖扰动后代谢适应性的介质。
DOI：
10.1080/21624054.2016.1151609
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Ghazi,Arjumand
中科院分区：
文献类型：
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作者：
Ratnappan,Ramesh;Ward,JordanD;Yamamoto,KeithR;Ghazi,Arjumand
以前，我们确定了一组核激素受体（NHRs），促进线虫的生殖干细胞（GSC）损失后的寿命。该组包括NHR-49，这是一种蠕虫蛋白，其功能类似于脊椎动物的PPARα，是脂质代谢的关键调节因子。我们发现，NHR-49/PPARα增强了生殖细胞去除后的线粒体β-氧化和脂肪酸去饱和，并通过协调增强这些过程使动物保持脂质稳态并延长寿命。在GSC消融动物中，NHR-49/PPARα表达升高，部分原因是由于NHR-16/FOXO 3A和TCER-1/TCERG 1，这两种其他保守的促长寿转录调节因子对无生殖细胞长寿至关重要。在探索其他促长寿NHR的作用时，我们发现其中一种NHR-71/HNF 4与NHR-49/PPARα发生物理相互作用。NHR-71/HNF 4对NHR-49/PPARα的β-氧化和去饱和靶标的表达没有广泛影响。但NHR-49/PPARα和NHR-71/HNF 4均是上调TNF-α-16/FOXO 3A和TCER-1/TCERG 1下游靶基因表达的关键。此外，nhr-49失活导致KRI-1（DAF-16/FOXO 3A和TCER-1/TCERG 1唯一已知的共同上游调节因子）的显着膜定位，这表明它可能在正反馈循环中运作以增强该途径的活性。这些数据强调了在代谢网络中作为节点的NHR之间的选择性相互作用如何赋予响应于不同生理刺激的功能特异性。
Previously, we identified a group of nuclear hormone receptors (NHRs) that promote longevity in the nematodeCaenorhabditis elegansfollowing germline-stem cell (GSC) loss. This group included NHR-49, the worm protein that performs functions similar to vertebrate PPARα, a key regulator of lipid metabolism. We showed that NHR-49/PPARα enhances mitochondrial β-oxidation and fatty acid desaturation upon germline removal, and through the coordinated enhancement of these processes allows the animal to retain lipid homeostasis and undergo lifespan extension. NHR-49/PPARα expression is elevated in GSC-ablated animals, in part, by DAF-16/FOXO3A and TCER-1/TCERG1, two other conserved, pro-longevity transcriptional regulators that are essential for germline-less longevity. In exploring the roles of the other pro-longevity NHRs, we discovered that one of them, NHR-71/HNF4, physically interacted with NHR-49/PPARα. NHR-71/HNF4 did not have a broad impact on the expression of β-oxidation and desaturation targets of NHR-49/PPARα. But, both NHR-49/PPARα and NHR-71/HNF4 were essential for the increased expression of DAF-16/FOXO3A- and TCER-1/TCERG1-downstream target genes. In addition,nhr-49inactivation caused a striking membrane localization of KRI-1, the only known common upstream regulator of DAF-16/FOXO3A and TCER-1/TCERG1, suggesting that it may operate in a positive feedback loop to potentiate the activity of this pathway. These data underscore how selective interactions between NHRs that function as nodes in metabolic networks, confer functional specificity in response to different physiological stimuli.