<scp>NHR</scp>‐49/<scp>HNF</scp>4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

Goh, Grace Ying Shyen; Winter, Johnathan J; Bhanshali, Forum; Doering, Kelsie R. S.; Lai, Regina; Lee, Kayoung; Veal, Elizabeth A.; Taubert, Stefan

doi:10.1111/acel.12743

Cited by 77 publications

(89 citation statements)

References 45 publications

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“…6A, B), we examined their genetic interactions. To determine whether hlh-30-30/TFEB and nhr-49/PPARA genetically function in the same pathway, we attempted to generate hlh-30(-); nhr-49(-) double mutants, but were unable to obtain them from genetic crosses suggesting synthetic lethality, consistent with a previous report (Goh et al, 2018). However, it was possible to construct nhr-49/PPARA (gain-of-function); hlh-30/TFEB (loss-of-function) double mutants.…”

Section: Hlh-30/tfeb Genetically Functions Downstream Of Nhr-49/ppar-supporting

confidence: 57%

“…NHR-49/PPAR-α is better known in C. elegans as a transcription factor that is important for the response to starvation (Van Gilst et al, 2005). However, recently NHR-49/PPAR-α was shown to mediate the defense response to exogenous oxidative stress (Goh et al, 2018;Hu et al, 2018). Thus, NHR-49/PPAR-α participates in host defense against biotic and abiotic stressors, and should be considered a key player in the organismal stress response alongside SKN-1/NRF, DAF-16/FOXO3, and HLH-30/TFEB (Blackwell et al, 2015;Lin et al, 2018;Tissenbaum, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies identified NHR-49, a nuclear receptor homologous to human PPAR-α and HNF4-α, as essential for fmo-2/FMO5 induction during exogenous oxidative stress (Goh et al, 2018;Hu et al, 2018). To examine the role of NHR-49/PPAR-α during infection, we checked fmo-2/FMO5 expression in nhr-49/PPARA null mutants (Liu et al, 1999;Van Gilst et al, 2005).…”

Section: Infection Induces Fmo-2/fmo5 Via Nhr-49/ppar-αmentioning

confidence: 99%

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NHR-49/PPAR-α and HLH-30/TFEB promote C. elegans host defense via a flavin-containing monooxygenase

Wani

Goswamy

Taubert

et al. 2020

Preprint

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During bacterial infection, the host is confronted with multiple overlapping signals that are integrated at the organismal level to produce defensive host responses. How multiple infection signals are sensed by the host and how they elicit the transcription of host defense genes is much less understood at the whole-animal level than at the cellular level. The model organism Caenorhabditis elegans is known to mount transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, but the regulation of such responses is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature. This signature was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, the mechanism of fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-α, which induced fmo-2/FMO5 and host defense cell non-autonomously. These findings for the first time reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal that FMOs are important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR-α in C. elegans, with important implications for innate host defense in higher organisms.

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Section: Hlh-30/tfeb Genetically Functions Downstream Of Nhr-49/ppar-supporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Infection Induces Fmo-2/fmo5 Via Nhr-49/ppar-αmentioning

confidence: 99%

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NHR-49/PPAR-α and HLH-30/TFEB promote C. elegans host defense via a flavin-containing monooxygenase

Wani

Goswamy

Taubert

et al. 2020

Preprint

Self Cite

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“…It has been reported that NHR-49 activity positively regulates expression of detoxification genes such as glutathione-S-transferase (gst-4). While we were writing the manuscript another study indicated that flavin mono-oxygenase (fmo-2) upregulation during oxidative stress was dependent on NHR-49 (Qi et al, 2017;Goh et al, 2018;Hu et al, 2018). Our study shows that NHR-49 regulates detoxification enzymes in the context of infection as well.…”

Section: Nhr-49 Nuclear Hormone Receptor Regulates Both Metabolic Andmentioning

confidence: 64%

Nuclear hormone receptor NHR-49 shapes immuno-metabolic response ofCaenorhabditis elegans to Enterococcus faecalisinfection

Dasgupta

Shashikanth

Bojanala

et al. 2019

Preprint

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Immune responses to pathogenic microbes include activation of resistance and tolerance mechanisms in the host both of which are energetically expensive. In this study, we show that C. elegans exposed to Gram positive bacteria Enterococcus faecalis and Staphylococcus aureus, rapidly utilizes lipid droplets, the major energy reserve in the nematode. Feeding on E. faecalis causes developmental arrest in C. elegans larvae and growth arrest in adults, pointing to starvation response. We find that nematode's early response to infection entails upregulation of 25 genes involved in lipid hydrolysis and downregulation of 13 lipid synthesis genes as early as 8 hours following exposure. We also show that lipid droplets play a protective role in C. elegans during infection. NHR-49, a PPARα ortholog, is required for E. faecalis induced betaoxidation of fatty acids and immune effector production. It regulates an immunometabolic axis required for survival of the nematode on E. faecalis. Our findings reveal a facet of nutritional immunity wherein lipid droplet homeostasis plays a central role in nematode microbe interactions.

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“…Goh and cols have already demonstrated that NHR-49 is not only a regulator of lipid metabolism, but also it is required for the activation of a protective transcriptional response to oxidative stress [ 67 ]. Here we showed that nhr-49(nr2041) is required for juglone resistance.…”

Section: Discussionmentioning

confidence: 99%

Ilex paraguariensis modulates fat metabolism in Caenorhabditis elegans through purinergic system (ADOR-1) and nuclear hormone receptor (NHR-49) pathways

et al. 2018

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Ilex paraguariensis is a well-known plant that is widely consumed in South America, primarily as a drink called mate. Mate is described to have stimulant and medicinal properties. Considering the potential anti-lipid effects of I. paraguariensis infusion, we used an extract of this plant as a possible modulator of fat storage to control lipid metabolism in worms. Herein, the I. paraguariensis-dependent modulation of fat metabolism in Caenorhabditis elegans was investigated. C. elegans were treated with I. paraguariensis aqueous extract (1 mg/ml) from L1 larvae stage until adulthood, to simulate the primary form of consumption. Expression of adipocyte triglyceride lipase 1 (ATGL-1) and heat shock protein 16.2, lipid accumulation through C1-BODIPY-C12 (BODIPY) lipid staining, behavioral parameters, body length, total body energy expenditure and overall survival were analyzed. Total body energy expenditure was determined by the oxygen consumption rate in N2, nuclear hormone receptor knockout, nhr-49(nr2041), and adenosine receptor knockout, ador-1(ox489) strains. Ilex paraguariensis extract increased ATGL-1 expression 20.06% and decreased intestinal BODIPY fat staining 63.36%, compared with the respective control group, without affecting bacterial growth and energetic balance, while nhr-49(nr2041) and ador-1(ox489) strains blocked the worm fat loss. In addition, I. paraguariensis increased the oxygen consumption in N2 worms, but not in mutant strains, increased N2 worm survival following juglone exposure, and did not alter hsp-16.2 expression. We demonstrate for the first time that I. paraguariensis can decrease fat storage and increase body energy expenditure in worms. These effects depend on the purinergic system (ADOR-1) and NHR-49 pathways. Ilex paraguariensis upregulated the expression of ATGL-1 to modulate fat metabolism. Furthermore, our data corroborates with other studies that demonstrate that C. elegans is a useful tool for studies of fat metabolism and energy consumption.

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

Cited by 77 publications

References 45 publications

NHR-49/PPAR-α and HLH-30/TFEB promote C. elegans host defense via a flavin-containing monooxygenase

NHR-49/PPAR-α and HLH-30/TFEB promote C. elegans host defense via a flavin-containing monooxygenase

Nuclear hormone receptor NHR-49 shapes immuno-metabolic response ofCaenorhabditis elegans to Enterococcus faecalisinfection

Ilex paraguariensis modulates fat metabolism in Caenorhabditis elegans through purinergic system (ADOR-1) and nuclear hormone receptor (NHR-49) pathways

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