Fatty Acid Desaturation Links Germ Cell Loss to Longevity Through NHR-80/HNF4 in C. elegans

Goudeau, Jérôme; Bellemin, Stéphanie; Toselli-Mollereau, Esther; Shamalnasab, Mehrnaz; Chen, Yiqun; Aguilaniu, Hugo

doi:10.1371/journal.pbio.1000599

Cited by 185 publications

(299 citation statements)

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“…In a previous study, Hugo Aguilaniu's laboratory reported that, in germline-less mutants too, NHR-80/HNF4 elevates the expression of enzymes responsible for converting a saturated fatty acid (SFA), stearic acid (SA, C16:0) into a mono-unsaturated fatty acid (MUFA), oleic acid (OA, C18:1n9). 21 We found that NHR-49/PPARa similarly controlled the expression of these desaturases in germline-less adults. Through lipidomic analyses, we further discovered that GSC-depleted adults showed an increase in unsaturated fatty acid (UFA) levels and a concomitant decrease in SFAs.…”

Section: Introductionmentioning

confidence: 66%

“…7,[15][16][17][18][19] Additionally, three members of the nuclear hormone receptor (NHR) family of transcription regulators, DAF-12/FXR, NHR-80/HNF4 and NHR-49/PPARa are important for GSC-less longevity. 7,[20][21][22] Multiple lines of evidence have indicated that these factors link lipid metabolism to reproductive stimuli and aging. DAF-16/FOXO3A, TCER-1/ TCERG1, SKN-1/NRF2 and DAF-12/FXR targets include lipid-metabolic genes, 15,19,20,[23][24][25] PHA-4/ FOXA-and HLH-30/TFEB-mediated enhancement of autophagy contributes to increased lipase activity 17,18 and NHR-80/HNF4 promotes fatty-acid desaturation in long-lived, GSC-less adults.…”

Section: Introductionmentioning

confidence: 99%

“…DAF-16/FOXO3A, TCER-1/ TCERG1, SKN-1/NRF2 and DAF-12/FXR targets include lipid-metabolic genes, 15,19,20,[23][24][25] PHA-4/ FOXA-and HLH-30/TFEB-mediated enhancement of autophagy contributes to increased lipase activity 17,18 and NHR-80/HNF4 promotes fatty-acid desaturation in long-lived, GSC-less adults. 21 However, the generegulatory network (GRN) in which these factors operate is poorly defined and it remains unclear how their activities allow an animal to not only survive the physiological disruption created by loss of GSCs but to convert it into a beneficial enhancement of health and lifespan.…”

Section: Introductionmentioning

confidence: 99%

“…22 nhr-49 mutants exhibit altered expression of enzymes that mediate fatty-acid desaturation, during development as well as fasting. 29,30 Fatty-acid desaturation is also regulated by NHR-80 that is structurally similar to HNF4 37 (we refer to NHR-80 as NHR-80/HNF4 in keeping with the terminology used in worm literature 21,27 ). In a previous study, Hugo Aguilaniu's laboratory reported that, in germline-less mutants too, NHR-80/HNF4 elevates the expression of enzymes responsible for converting a saturated fatty acid (SFA), stearic acid (SA, C16:0) into a mono-unsaturated fatty acid (MUFA), oleic acid (OA, C18:1n9).…”

Section: Introductionmentioning

confidence: 99%

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Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

Ratnappan

Ward

Ghazi

2016

Worm

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Previously, we identified a group of nuclear hormone receptors (NHRs) that promote longevity in the nematode Caenorhabditis elegans following germline-stem cell (GSC) loss. This group included NHR-49, the worm protein that performs functions similar to vertebrate PPARa, a key regulator of lipid metabolism. We showed that NHR-49/PPARa enhances mitochondrial b-oxidation and fatty acid desaturation upon germline removal, and through the coordinated enhancement of these processes allows the animal to retain lipid homeostasis and undergo lifespan extension. NHR-49/ PPARa expression is elevated in GSC-ablated animals, in part, by DAF-16/FOXO3A and TCER-1/ TCERG1, two other conserved, pro-longevity transcriptional regulators that are essential for germline-less longevity. In exploring the roles of the other pro-longevity NHRs, we discovered that one of them, NHR-71/HNF4, physically interacted with NHR-49/PPARa. NHR-71/HNF4 did not have a broad impact on the expression of b-oxidation and desaturation targets of NHR-49/PPARa. But, both NHR-49/PPARa and NHR-71/HNF4 were essential for the increased expression of DAF-16/ FOXO3A-and TCER-1/TCERG1-downstream target genes. In addition, nhr-49 inactivation caused a striking membrane localization of KRI-1, the only known common upstream regulator of DAF-16/ FOXO3A and TCER-1/TCERG1, suggesting that it may operate in a positive feedback loop to potentiate the activity of this pathway. These data underscore how selective interactions between NHRs that function as nodes in metabolic networks, confer functional specificity in response to different physiological stimuli.

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Section: Introductionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

Ratnappan

Ward

Ghazi

2016

Worm

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“…This effect occurred already after short-term exposure of the worms to 10 µM 17,18-EEQ, whereas long-term feeding and much higher concentrations were required to achieve similar effects with AA or EPA. Also other authors found that high concentrations and a minimal time of about 24 h are required to restore the phenotype of fat-3 mutants by C20-PUFA supplementation [43][44][45][46][47][48]. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity already under normoxic conditions and was effective not only with the mutant but to a lesser extent also with wild-type worms.…”

Section: Discussionmentioning

confidence: 98%

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Keller

Ellieva

Dengke

et al. 2014

Biochemical Journal

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SHORT TITLE:CYP-13A12 of C. elegans is a PUFA-epoxygenase 4 SYNOPSISA specific behavioural response of Caenorhabditis elegans, the rapid increase of locomotion in response to anoxia/reoxygenation called the O2-ON response, has been used to model key aspects of ischemia/reperfusion injury. A genetic suppressor screen demonstrated a direct causal role of CYP-13A12 in this response and suggested that CYP-eicosanoids, which in mammals influence the contractility of cardiomyocytes and vascular smooth muscle cells, might function in C. elegans as specific regulators of the body muscle cell activity. Here we show that co-expression of CYP-13A12 with the NADPH-CYP-reductase EMB-8 in insect cells resulted in the reconstitution of an active microsomal monooxygenase system that metabolised EPA (eicosapentaenoic acid) and also AA (arachidonic acid) to specific sets of regioisomeric epoxy and hydroxy derivatives. Main products included 17,18-EEQ (epoxyeicosatetraenoic acid) from EPA and 14,15-EET (epoxyeicosatrienoic acid) from AA. Locomotion assays showed that the defective O2-ON response of C20-PUFA-deficient, ∆ -12 and ∆ -6 fatty acid desaturase mutants (fat-2 and fat-3, respectively) can be restored by feeding the nematodes AA or EPA, but not ETYA (eicosatetraynoic acid), a non-metabolisable AAanalogue. Already short-term incubation with 17,18-EEQ was sufficient to rescue the impaired locomotion of the fat-3 strain. The endogenous level of free 17,18-EEQ declined during anoxia and was rapidly restored in response to reoxygenation. Based on these results, we suggest that CYP-dependent eicosanoids such as 17,18-EEQ function as signalling molecules in the regulation of the O2-ON response in C. elegans. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity already under normoxic conditions and was effective not only with C20-PUFA mutants but to a lesser extent also with wild-type worms. KEYWORDS:Eicosanoids; Polyunsaturated fatty acids; Caenorhabditis elegans; Cytochrome P450; Reoxygenation; 17,18-EEQ ABBREVIATIONS USED: AA, arachidonic acid; CID, collision-induced dissociation; COD, carbon monoxide difference; CPR, NADPH-CYP reductase; CYP, cytochrome P450; DiHETE, dihydroxyeicosatetraenoic acid; DTT, dithiothreitol; EGL, egg laying defect; EGLN, EGL nine; EEQ, epoxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; ETYA, eicosatetraynoic acid; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; HEET, hydroxyepoxyeicosatrienoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HIF, hypoxia inducible factor; LC, liquid chromatography; MC, pharyngeal marginal cell; MS, mass spectrometry; NGM, nematode growth medium; PUFA, polyunsaturated fatty acid; RP, reversed-phase 5 INTRODUCTIONOxygen deprivation upon restriction of blood supply followed by reperfusion and concomitant reoxygenation causes tissue injury and is involved in the initiation of various human pathologies including ischemic stroke, myocardial infarction, and ac...

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The mystery of C. elegans aging: An emerging role for fat

Ackerman

Gems

2012

BioEssays

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New C. elegans studies imply that lipases and lipid desaturases can mediate signaling effects on aging. But why might fat homeostasis be critical to aging? Could problems with fat handling compromise health in nematodes as they do in mammals? The study of signaling pathways that control longevity could provide the key to one of the great unsolved mysteries of biology: the mechanism of aging. But as our view of the regulatory pathways that control aging grows ever clearer, the nature of aging itself has, if anything, grown more obscure. In particular, focused investigations of the oxidative damage theory have raised questions about an old assumption: that a fundamental cause of aging is accumulation of molecular damage. Could fat dyshomeostasis instead be critical?

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Fatty Acid Desaturation Links Germ Cell Loss to Longevity Through NHR-80/HNF4 in C. elegans

Abstract: Lifespan extension induced by germline ablation in C. elegans is regulated by the nuclear hormone receptor NHR-80 in a process that requires the production of oleic acid by activation of the lipid desaturase FAT-6/SCD1.

Cited by 185 publications

References 33 publications

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

The mystery of C. elegans aging: An emerging role for fat

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