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NHR-49/HNF4 Integrates Regulation of Fatty Acid Metabolism With a Protective Transcriptional Response to Oxidative Stress and Fasting

By March 30, 2018No Comments

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 This week we profile a recent publication in Aging Cell from the laboratory of
Dr. Stefan Taubert
(back row) at the Centre for Molecular Medicine and Therapeutics.

Can you provide a brief overview of your lab’s current research focus?

Animals, including us humans, have evolved complex way of controlling gene expression. Gene regulation commonly occurs at the level of transcription, which requires sequence specific transcription factors, regulatory DNA elements, and transcriptional coregulators such as the Mediator complex. We are particularly interested in in studying how animals rewire transcription in response to environmental stresses such as starvation, oxidative stress, and hypoxia. These stresses are of great biomedical interest because they occur in various diseases states, including diabetes, cancer, and neurodegenerative diseases [1-3]. A better understanding of how these stresses arise and how a cells and organisms can cope with them may lead to new therapeutic strategies. In our lab, we use the nematode worm Caenorhabditis elegans (C. elegans), a powerful model organism to decipher stress response regulatory networks. We also extend findings from our C. elegans studies into pre-clinical mouse and human cell culture studies.

What is the significance of the findings in this publication?

Oxidative stress occurs when excess reactive oxygen species (ROS), ubiquitous byproducts of aerobic respiration, are produced in cells at levels that overwhelm the normal antioxidant capacity. Oxidative stress causes damage to proteins, lipids, and DNA, which contributes to many pathological conditions including diabetes, neurodegenerative diseases, and cancer, as well as aging [4]. Hence, ROS levels need to be tightly controlled. Until recently, the C. elegans transcription factor SKN-1 and its mammalian counterparts Nrf1/2/3 were widely considered the master regulators that coordinate the ROS response [5]. Conversely, little was known about other, SKN-1-independent oxidative stress responses; nevertheless, our and other’ past work clearly indicated that they exist and are important [6-8]. Our study aimed to map the molecular components of this regulatory mechanism. Using a combination of genetic, molecular, and biochemical methods, we found that a subunit of the Mediator complex, MDT-15, and the Nuclear Hormone Receptor NHR-49 are novel regulators of oxidative stress responses [9]. This was surprising as both proteins were primarily known as regulators of lipid metabolism [10,11]. However, we found that, when exposed to organic peroxide, MDT-15 and NHR-49 activate a suite of non-lipid metabolism genes. Importantly, these two transcriptional regulators, as well as some of their targets, are required in worms for organismal resistance to oxidative stress; that is, when these genes are mutated, the worms die faster in conditions of excess ROS. Moreover, we found similar regulatory and functional requirements for this new genetic pathway when worms experience another, stress, namely starvation. Thus, this pathway appears to be a multi-stress response system. Lastly, we tried to determine how stress activates this new response pathway; we found that NHR-49 protein levels increase in response to oxidative stress, through a mechanisms that did not require the “classical” stress responsive kinases PMK-1 and SEK-1 (which are required to activate SKN-1/Nrf; [5]). In sum, our data have identified that regulatory and functional core of new stress response network that is molecularly distinct from the well characterized SKN-1/Nrf pathway.

I should point out that this was a really fruitful collaboration with the lab of Dr. Elizabeth Veal, at the University of Newcastle upon Tyne in the UK.

What are the next steps for this research?

In the future, we would like to describe in detail the new stress response network centered by NHR-49 and MDT-15 to understand what activates these regulators in oxidative stress conditions. We speculate that kinases and other signaling molecules activate these proteins when worms encounter environmental stress and will perform functional genetic screens to identify such molecules. Moreover, SKN-1, NHR-49, and MDT-15 are all conserved in humans; however, whether the orthologs of NHR-49 and MDT-15 regulate stress responses in mammalian organisms or cells has not yet been tested. If this were the case, such knowledge could be used to discover inhibitory molecules that could be used in conjunction with already developed Nrf inhibitors to treat e.g. cancers. Hence, our work on understanding on how cells adapt or defend to the oxidant injury may have therapeutic implications for diseases.

This research was funded by:

Canadian Institute of Health Research (CIHR) Project grant PJT-153199 and Natural Sciences and Engineering Research Council (NSERC) Discovery Grant RGPIN 386398-13.


[1]         E.B. Rankin, A.J. Giaccia, Hypoxic control of metastasis, Science. 352 (2016) 175–180. doi:10.1126/science.aaf4405.

[2]         G. Drews, P. Krippeit-Drews, M. Düfer, Oxidative stress and beta-cell dysfunction, Pflugers Arch. 460 (2010) 703–718. doi:10.1007/s00424-010-0862-9.

[3]         E. Piskounova, M. Agathocleous, M.M. Murphy, Z. Hu, S.E. Huddlestun, Z. Zhao, et al., Oxidative stress inhibits distant metastasis by human melanoma cells, Nature. 527 (2015) 186–191. doi:10.1038/nature15726.

[4]         D.E. Shore, G. Ruvkun, A cytoprotective perspective on longevity regulation, Trends Cell Biol. 23 (2013) 409–420. doi:10.1016/j.tcb.2013.04.007.

[5]         T.K. Blackwell, M.J. Steinbaugh, J.M. Hourihan, C.Y. Ewald, M. Isik, SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans, Free Radic. Biol. Med. 88 (2015) 290–301. doi:10.1016/j.freeradbiomed.2015.06.008.

[6]         H.M. Crook-McMahon, M. Oláhová, E.L. Button, J.J. Winter, E.A. Veal, Genome-wide screening identifies new genes required for stress-induced phase 2 detoxification gene expression in animals, BMC Biol. 12 (2014) 64. doi:10.1186/s12915-014-0064-6.

[7]         R.P. Oliveira, J.P. Abate, K. Dilks, J. Landis, J. Ashraf, C.T. Murphy, et al., Condition-adapted stress and longevity gene regulation byCaenorhabditis elegansSKN-1/Nrf, Aging Cell. 8 (2009) 524–541. doi:10.1111/j.1474-9726.2009.00501.x.

[8]         G.Y.S. Goh, K.L. Martelli, K.S. Parhar, A.W.L. Kwong, M.A. Wong, A. Mah, et al., The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans, Aging Cell. 13 (2014) 70–79. doi:10.1111/acel.12154.

[9]         G.Y.S. Goh, J.J. Winter, F. Bhanshali, K.R.S. Doering, R. Lai, K. Lee, et al., NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting, Aging Cell. (2018). doi:10.1111/acel.12743.

[10]       M.R. Van Gilst, H. Hadjivassiliou, A. Jolly, K.R. Yamamoto, Nuclear Hormone Receptor NHR-49 Controls Fat Consumption and Fatty Acid Composition in C. elegans, PLoS Biol. 3 (2005) e53. doi:10.1371/journal.pbio.0030053.st001.

[11]       S. Taubert, M.R. Van Gilst, M. Hansen, K.R. Yamamoto, A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans, Genes Dev. 20 (2006) 1137–1149. doi:10.1101/gad.1395406.

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