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Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence.

Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operaña TN, Esmaillie R, Blackwell TK - Elife (2015)

Bottom Line: Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction.We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids.This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, Boston, United States.

ABSTRACT
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

No MeSH data available.


Related in: MedlinePlus

Representative ORO staining images with quantification.Representative images divided into approximate quintiles, ordered by mean pixel intensity, are shown for each strain. BF images are presented on the left and background subtracted images with quantification on the right. (A) glp-1(bn18ts) and skn-1(zu135) mutants. (B) glp-1(ts) mutants treated with skn-1 and sbp-1 RNAi. Increased staining was observed both with skn-1 mutants and skn-1 RNAi. RNAi against sbp-1, which is required for lipogenesis (Yang et al., 2006), decreases ORO staining in both WT and glp-1(ts) genetic backgrounds. (C) glp-1(e2141ts) and daf-16(mu86) mutants. Numbers indicate mean pixel intensity above background (see ‘Materials and methods’ for additional details).DOI:http://dx.doi.org/10.7554/eLife.07836.012
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fig5s1: Representative ORO staining images with quantification.Representative images divided into approximate quintiles, ordered by mean pixel intensity, are shown for each strain. BF images are presented on the left and background subtracted images with quantification on the right. (A) glp-1(bn18ts) and skn-1(zu135) mutants. (B) glp-1(ts) mutants treated with skn-1 and sbp-1 RNAi. Increased staining was observed both with skn-1 mutants and skn-1 RNAi. RNAi against sbp-1, which is required for lipogenesis (Yang et al., 2006), decreases ORO staining in both WT and glp-1(ts) genetic backgrounds. (C) glp-1(e2141ts) and daf-16(mu86) mutants. Numbers indicate mean pixel intensity above background (see ‘Materials and methods’ for additional details).DOI:http://dx.doi.org/10.7554/eLife.07836.012

Mentions: (A) Functional map of lipid metabolism gene expression. Left columns show the effects of GSC absence (GSC(−) vs WT) and right columns the effects of skn-1 RNAi in GSC(−) animals. SKN-1 regulates genes involved in fatty acid (FA) oxidation, breakdown of triacylglycerols (TAG) to free FAs, production of mono- and poly-unsaturated FAs (MUFA, PUFA), and FA transport. Color coding reflects relative representation in RNA-seq data, with blue and yellow indicating increased and decreased expression, respectively. (B–E) Increased fat levels in glp-1(ts) and skn-1 mutants but not daf-16 mutants. (D, E) glp-1(ts) refers to glp-1(e2141ts). Representative 40× differential interference contrast (DIC) images of fixed ORO-stained worms are shown in (B, D), with quantification provided in (C, E). Additional images and quantification are provided in Figure 5—figure supplement 1. Data are represented as mean ± SEM. Numbers above bars denote sample size. p < 0.001***.


Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence.

Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operaña TN, Esmaillie R, Blackwell TK - Elife (2015)

Representative ORO staining images with quantification.Representative images divided into approximate quintiles, ordered by mean pixel intensity, are shown for each strain. BF images are presented on the left and background subtracted images with quantification on the right. (A) glp-1(bn18ts) and skn-1(zu135) mutants. (B) glp-1(ts) mutants treated with skn-1 and sbp-1 RNAi. Increased staining was observed both with skn-1 mutants and skn-1 RNAi. RNAi against sbp-1, which is required for lipogenesis (Yang et al., 2006), decreases ORO staining in both WT and glp-1(ts) genetic backgrounds. (C) glp-1(e2141ts) and daf-16(mu86) mutants. Numbers indicate mean pixel intensity above background (see ‘Materials and methods’ for additional details).DOI:http://dx.doi.org/10.7554/eLife.07836.012
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4541496&req=5

fig5s1: Representative ORO staining images with quantification.Representative images divided into approximate quintiles, ordered by mean pixel intensity, are shown for each strain. BF images are presented on the left and background subtracted images with quantification on the right. (A) glp-1(bn18ts) and skn-1(zu135) mutants. (B) glp-1(ts) mutants treated with skn-1 and sbp-1 RNAi. Increased staining was observed both with skn-1 mutants and skn-1 RNAi. RNAi against sbp-1, which is required for lipogenesis (Yang et al., 2006), decreases ORO staining in both WT and glp-1(ts) genetic backgrounds. (C) glp-1(e2141ts) and daf-16(mu86) mutants. Numbers indicate mean pixel intensity above background (see ‘Materials and methods’ for additional details).DOI:http://dx.doi.org/10.7554/eLife.07836.012
Mentions: (A) Functional map of lipid metabolism gene expression. Left columns show the effects of GSC absence (GSC(−) vs WT) and right columns the effects of skn-1 RNAi in GSC(−) animals. SKN-1 regulates genes involved in fatty acid (FA) oxidation, breakdown of triacylglycerols (TAG) to free FAs, production of mono- and poly-unsaturated FAs (MUFA, PUFA), and FA transport. Color coding reflects relative representation in RNA-seq data, with blue and yellow indicating increased and decreased expression, respectively. (B–E) Increased fat levels in glp-1(ts) and skn-1 mutants but not daf-16 mutants. (D, E) glp-1(ts) refers to glp-1(e2141ts). Representative 40× differential interference contrast (DIC) images of fixed ORO-stained worms are shown in (B, D), with quantification provided in (C, E). Additional images and quantification are provided in Figure 5—figure supplement 1. Data are represented as mean ± SEM. Numbers above bars denote sample size. p < 0.001***.

Bottom Line: Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction.We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids.This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, Boston, United States.

ABSTRACT
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

No MeSH data available.


Related in: MedlinePlus