Research Article: NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

Date Published: March 05, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Grace Y. S. Goh, Johnathan J. Winter, Forum Bhanshali, Kelsie R. S. Doering, Regina Lai, Kayoung Lee, Elizabeth A. Veal, Stefan Taubert.


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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The ability to respond to acute stress conditions is vital to prevent or limit organismal damage. For instance, transcriptional responses promote adaptation and survival under stress conditions. Impaired stress responses contribute to human age‐related diseases such as diabetes and neurodegenerative disorders (Hetz, Chevet & Harding, 2013; Lin & Beal, 2006), and likely also contribute to aging (Hekimi, Lapointe & Wen, 2011; Shore & Ruvkun, 2013). However, these adaptive responses also protect pathogens and cancer cells against cytotoxic drugs and the immune system (Leprivier, Rotblat, Khan, Jan & Sorensen, 2015; Rankin & Giaccia, 2016). Accordingly, there is widespread interest in defining the mechanisms involved in coordinating these transcriptional responses.

NHR‐49 is a critical regulator of lipid metabolism and longevity (Burkewitz et al., 2015; Chamoli, Singh, Malik & Mukhopadhyay, 2014; Folick et al., 2015; Khan et al., 2013; Ratnappan et al., 2014; Seah et al., 2016), while related nuclear receptors, HNF4 and PPARα, are therapeutic targets that share at least some of these functions in mammals. Here, we show that NHR‐49 is also vital for an adaptive transcriptional response to the organic peroxide tBOOH. This response includes the induction of the flavin‐containing monooxygenase fmo‐2, which is important for dietary restriction‐induced longevity and resistance to several stresses (Leiser et al., 2015), and two other genes, K05B2.4 and sodh‐1, that we reveal here to be important for resistance to organic peroxide. Moreover, we find that nhr‐49 is also required for the induction of tBOOH‐induced genes by acute fasting. Collectively, our data suggest that, in addition to its role in regulating lipid metabolism, NHR‐49 participates in a cytoprotective acute stress response program that functions parallel to and independently of SKN‐1/Nrf2 and HLH‐30/TFEB signaling (Blackwell et al., 2015; Lapierre et al., 2013). This raises the possibility that NHR‐49’s pro‐longevity function, for example in glp‐1 mutants (Ratnappan et al., 2014), may involve modulating both lipid metabolism and stress defenses (Figure 6).

None declared.

EAV and ST conceptualized the study; GYSG, JJW, EAV, KRSD, FB, RL, and KL investigated the study; ST and EAV wrote the original draft; ST, EAV, GG, and JJW wrote the manuscript and helped in reviewing and editing the manuscript; EAV and ST acquired funding; EAV and ST supervised the experiments.




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