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

Lookup NU author(s): Johnathan Winter, Dr Elizabeth VealORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. The C. elegans nuclear hormone receptor, NHR-49, is a well-established regulator of lipid metabolism. Here we reveal that NHR-49 is also essential for a common transcriptional response to organic peroxide and fasting that includes the pro-longevity gene fmo-2. These NHR-49-dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, increasing oxidative stress resistance, and potentially contributing to NHR-49-dependent increases in lifespan. Similar to its role in lipid metabolism, NHR-49 requires the Mediator subunit mdt-15 to promote stress-induced gene expression. However, our discovery that organic peroxide increases NHR-49 protein levels, reveals a new way to regulate NHR-49 activity. Moreover, activation of the p38 MAPK, PMK-1, is also important for peroxide-induced expression of some NHR-49-dependent genes, including fmo-2. Together these findings establish a new role for the HNF4/PPARa-related NHR-49 as a stress-activated regulator of cytoprotective gene expression.

Publication metadata

Author(s): Goh G, Winter JJ, Bhanshali F, Lai R, Lee K, Taubert S, Veal EA

Publication type: Article

Publication status: Published

Journal: Aging Cell

Year: 2018

Volume: 17

Issue: 3

Print publication date: 01/06/2018

Online publication date: 05/03/2018

Acceptance date: 20/01/2018

Date deposited: 08/02/2019

ISSN (print): 1474-9718

ISSN (electronic): 1474-9726

Publisher: Wiley-Blackwell

URL: https://doi.org/10.1111/acel.12743

DOI: 10.1111/acel.12743

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