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

ABSTRACT: 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 a (PPARa), 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 monoxygenase. These NHR-49-dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, and two of them contribute to increased oxidative stress resistance in wild-type worms and long-lived glp-1 mutants. 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. Similarly, activation of the p38 MAPK, PMK-1, which is important for adaptation to a variety of stresses, is only important for peroxide-induced expression of a subset of NHR-49-dependent genes, including fmo-2. Notably, we find that organic peroxide increases NHR-49 protein levels, apparently by a post-transcriptional mechanism that does not require PMK-1 activation. Together these findings establish a new role for the HNF4/PPARa-related NHR-49 as a stress-activated regulator of cytoprotective gene expression.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE107799 | GEO | 2018/03/05

REPOSITORIES: GEO

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Project description:Animals can thrive on variable food resources as a result of autonomous processes and beneficial relationships with their gut microbes. Food intake elicits major physiological changes, which are compensated with transient systemic responses that maintain homeostasis in the organism. This integration of external information occurs through cellular sensory elements, such as nuclear receptors, which modulate gene expression in response to specific cues. Given the importance of the germline stem cells (GSCs) for the development of the germ line and the continuity of the species, it is reasonable to assume that GSCs might be shielded from the negative influence of environmental perturbations. To our knowledge, however, there are no mechanisms reported that protect proliferating germ cells from harmful dietary metabolites. Using Caenorhabditis elegans as a model, we report that the somatic activity of the conserved nuclear receptor nhr-114/HNF4 protects GSC divisions and GSC integrity from dietary metabolites. In the absence of nhr-114 and on certain bacterial diets, otherwise somatically normal animals accumulate germ cell division defects during development and become sterile. We find that in nhr-114(-) animals the induction of germline defects and sterility depends on the bacterial metabolic status with respect to the essential amino acid tryptophan. This illustrates an animal-microbe interaction in which somatic nuclear receptor activity preserves the germline by buffering against dietary metabolites, likely through a somatic detoxifying response. Overall, our findings uncover an unprecedented and presumably evolutionary conserved soma-to-germline axis of communication that maintains reproductive robustness on variable food resources. Trasncriptional profiles of adult sterile nhr-114(RNAi) animals were compared to those of sterile glp-1(q224ts) animals. Independently, the transcriptional profiles of wild type animals fed an OP50 diet supplemented with Tryptophan was compared to wild type animals fed a standard OP50 diet.

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

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