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The ?-3 fatty acid ?-linolenic acid extends Caenorhabditis elegans lifespan via NHR-49/PPAR? and oxidation to oxylipins.

ABSTRACT: The dietary intake of ?-3 polyunsaturated fatty acids has been linked to a reduction in the incidence of aging-associated disease including cardiovascular disease and stroke. Additionally, long-lived Caenorhabditis elegans glp-1 germ line-less mutant animals show a number of changes in lipid metabolism including the increased production of the ?-3 fatty acid, ?-linolenic acid (ALA). Here, we show that the treatment of C. elegans with ALA produces a dose-dependent increase in lifespan. The increased longevity of the glp-1 mutant animals is known to be dependent on both the NHR-49/PPAR? and SKN-1/Nrf2 transcription factors, although the mechanisms involved are incompletely understood. We find that ALA treatment increased the lifespan of wild-type worms and that these effects required both of these transcription factors. Specifically, NHR-49 was activated by ALA to promote the expression of genes involved in the ?-oxidation of lipids, whereas SKN-1 is not directly activated by ALA, but instead, the exposure of ALA to air results in the oxidation of ALA to a group of compounds termed oxylipins. At least one of the oxylipins activates SKN-1 and enhances the increased longevity resulting from ALA treatment. The results show that ?-3 fatty acids inhibit aging and that these effects could reflect the combined effects of the ?-3 fatty acid and the oxylipin metabolites. The benefits of ?-3 fatty acid consumption on human health may similarly involve the production of oxylipins, and differences in oxylipin conversion could account for at least part of the variability found between observational vs. interventional clinical trials.

SUBMITTER: Qi W

PROVIDER: S-EPMC5595674 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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The ω-3 fatty acid α-linolenic acid extends Caenorhabditis elegans lifespan via NHR-49/PPARα and oxidation to oxylipins.

Qi Wenbo W Gutierrez Gloria E GE Gao Xiaoli X Dixon Hong H McDonough Joe A JA Marini Ann M AM Fisher Alfred L AL

Aging cell 20170803 5

The dietary intake of ω-3 polyunsaturated fatty acids has been linked to a reduction in the incidence of aging-associated disease including cardiovascular disease and stroke. Additionally, long-lived Caenorhabditis elegans glp-1 germ line-less mutant animals show a number of changes in lipid metabolism including the increased production of the ω-3 fatty acid, α-linolenic acid (ALA). Here, we show that the treatment of C. elegans with ALA produces a dose-dependent increase in lifespan. The increa ...[more]

PMID: 28772063

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Project description:Nuclear hormone receptors (NHRs) are transcription factors that regulate numerous physiological and developmental processes and represent important drug targets. NHR-49, an ortholog of Hepatocyte Nuclear Factor 4 (HNF4), has emerged as a key regulator of lipid metabolism and life span in the nematode worm Caenorhabditis elegans. However, many aspects of NHR-49 function remain poorly understood, including whether and how it regulates individual sets of target genes and whether its activity is modulated by a ligand. A recent study identified three gain-of-function (gof) missense mutations in nhr-49 (nhr-49(et7), nhr-49(et8), and nhr-49(et13), respectively). These substitutions all affect the ligand-binding domain (LBD), which is critical for ligand binding and protein interactions. Thus, these alleles provide an opportunity to test how three specific residues contribute to NHR-49 dependent gene regulation. We used computational and molecular methods to delineate how these mutations alter NHR-49 activity. We find that despite originating from a screen favoring the activation of specific NHR-49 targets, all three gof alleles cause broad upregulation of NHR-49 regulated genes. Interestingly, nhr-49(et7) and nhr-49(et8) exclusively affect nhr-49 dependent activation, whereas the nhr-49(et13) surprisingly affects both nhr-49 mediated activation and repression, implicating the affected residue as dually important. We also observed phenotypic non-equivalence of these alleles, as they unexpectedly caused a long, short, and normal life span, respectively. Mechanistically, the gof substitutions altered neither protein interactions with the repressive partner NHR-66 and the coactivator MDT-15 nor the subcellular localization or expression of NHR-49. However, in silico structural modeling revealed that NHR-49 likely interacts with small molecule ligands and that the missense mutations might alter ligand binding, providing a possible explanation for increased NHR-49 activity. In sum, our findings indicate that the three nhr-49 gof alleles are non-equivalent, and highlight the conserved V411 residue affected by et13 as critical for gene activation and repression alike.

Dataset Information

The ?-3 fatty acid ?-linolenic acid extends Caenorhabditis elegans lifespan via NHR-49/PPAR? and oxidation to oxylipins.

Publications

The ω-3 fatty acid α-linolenic acid extends Caenorhabditis elegans lifespan via NHR-49/PPARα and oxidation to oxylipins.

Similar Datasets

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