NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting.
NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting.
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DOI：
10.1111/acel.12743
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发表时间：
2018-06
期刊：
影响因子：
7.8
通讯作者：
Taubert S
中科院分区：
文献类型：
--
作者：
Goh GYS;Winter JJ;Bhanshali F;Doering KRS;Lai R;Lee K;Veal EA;Taubert S
内源性和外源性应激引起限制损伤和促进细胞/生物体存活的转录反应。与哺乳动物肝细胞核因子4（HNF 4）和过氧化物酶体增殖物激活受体α（PPARα）一样，秀丽隐杆线虫NHR-49是一种公认的脂质代谢调节剂。在这里，我们揭示了NHR-49对于激活有机过氧化物和禁食常见的转录反应是必不可少的，其中包括促长寿基因fmo-2/含黄素的单加氧酶。这些NHR-49依赖性应激反应基因在长寿的glp-1/notch受体突变体中也上调，其中两个对野生型和长寿的glp-1突变体蠕虫的氧化应激抗性做出了关键贡献。与其在脂质代谢中的作用类似，NHR-49需要介体亚基mdt-15来促进应激诱导的基因表达。然而，NHR-49的作用独立于转录因子hlh-30/TFEB，后者也促进fmo-2的表达。我们发现，p38 MAPK，PMK-1的激活对于适应各种压力很重要，对于过氧化物诱导的NHR-49依赖性基因（包括fmo-2）的表达也很重要。然而，有机过氧化物通过不需要PMK-1激活的转录后机制增加NHR-49蛋白水平。总之，这些发现确立了HNF 4/PPARα相关NHR-49作为细胞保护基因表达的应激激活调节因子的新作用。
Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator‐activated receptor α (PPARα), Caenorhabditis elegans NHR‐49 is a well‐established regulator of lipid metabolism. Here, we reveal that NHR‐49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro‐longevity gene fmo‐2/flavin‐containing monooxygenase. These NHR‐49‐dependent, stress‐responsive genes are also upregulated in long‐lived glp‐1/notch receptor mutants, with two of them making critical contributions to the oxidative stress resistance of wild‐type and long‐lived glp‐1 mutants worms. Similar to its role in lipid metabolism, NHR‐49 requires the mediator subunit mdt‐15 to promote stress‐induced gene expression. However, NHR‐49 acts independently from the transcription factor hlh‐30/TFEB that also promotes fmo‐2 expression. We show that activation of the p38 MAPK, PMK‐1, which is important for adaptation to a variety of stresses, is also important for peroxide‐induced expression of a subset of NHR‐49‐dependent genes that includes fmo‐2. However, organic peroxide increases NHR‐49 protein levels, by a posttranscriptional mechanism that does not require PMK‐1 activation. Together, these findings establish a new role for the HNF4/PPARα‐related NHR‐49 as a stress‐activated regulator of cytoprotective gene expression.
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DOI：
10.18632/aging.100604
发表时间：
2013-10
期刊：
Aging
影响因子：
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作者：
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影响因子：
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DOI：
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发表时间：
2008-12-16
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
7.8
作者：
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通讯作者：
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