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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

FA desaturation is required for GSC(−) stress resistance.glp-1(ts) and control day-1 adult worms treated with lipl-3, sbp-1, fat-6/7 mix, skn-1, or empty vector RNAi were exposed to 5 mM AS. Knockdown of lipl-3 (A, B), and either sbp-1 (A, B) or fat-6/7 (C, D) abolished the increase in AS resistance seen in glp-1(ts) animals. (B, D) Data are represented as mean ± SEM. p < 0.05*; p < 0.01**; p < 0.001***. The interaction between glp-1(ts) and fat-6/7, lipl-3, sbp-1, and skn-1 were significant (p < 0.001). Additional information and statistics are provided in Table 2.DOI:http://dx.doi.org/10.7554/eLife.07836.018
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fig6s3: FA desaturation is required for GSC(−) stress resistance.glp-1(ts) and control day-1 adult worms treated with lipl-3, sbp-1, fat-6/7 mix, skn-1, or empty vector RNAi were exposed to 5 mM AS. Knockdown of lipl-3 (A, B), and either sbp-1 (A, B) or fat-6/7 (C, D) abolished the increase in AS resistance seen in glp-1(ts) animals. (B, D) Data are represented as mean ± SEM. p < 0.05*; p < 0.01**; p < 0.001***. The interaction between glp-1(ts) and fat-6/7, lipl-3, sbp-1, and skn-1 were significant (p < 0.001). Additional information and statistics are provided in Table 2.DOI:http://dx.doi.org/10.7554/eLife.07836.018

Mentions: We investigated whether accumulation of yolk-associated lipids might induce SKN-1 to mount a protective response. Supporting this idea, when the oocyte-specific yolk receptor rme-2 is knocked down, yolk accumulates to high levels (Grant and Hirsh, 1999), and in the intestine, SKN-1 accumulates in nuclei and its target gene gst-4 is activated (Figure 6C–F). Additionally, rme-2 RNAi increased stress resistance in a skn-1-dependent manner (Figure 6G and Table 2). When de novo lipogenesis was prevented by knockdown of the SREBP1 ortholog sbp-1 (Yang et al., 2006), SKN-1::GFP failed to accumulate in intestinal nuclei in response to GSC inhibition (Figure 6H,I), but not oxidative stress (Figure 6—figure supplement 2A) or reduced IIS (daf-2 mutants, Figure 6—figure supplement 2B). The sbp-1 lipogenesis defect can be rescued by supplementation with 600 µM OA (Yang et al., 2006), which is the most abundant FA in olive oil, chicken egg yolk, and human adipose tissue (National Research Council, 1976; Kokatnur et al., 1979). In C. elegans, the abundance of OA is increased in GSC(−) animals, and its synthesis by the FA desaturases, FAT-6 and FAT-7 (SCD orthologs), is required for GSC(−) lifespan extension (Goudeau et al., 2011). fat-6/7 were also required for SKN-1 to accumulate in nuclei after GSC inhibition (Figure 6J). Moreover, in GSC(−) animals subjected to sbp-1 RNAi, SKN-1 nuclear accumulation was fully restored by OA supplementation (Figure 6H,I). Consistent with their importance for SKN-1 function, sbp-1 and fat-6/7 were required for GSC absence to increase stress resistance (Figure 6—figure supplement 3).


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)

FA desaturation is required for GSC(−) stress resistance.glp-1(ts) and control day-1 adult worms treated with lipl-3, sbp-1, fat-6/7 mix, skn-1, or empty vector RNAi were exposed to 5 mM AS. Knockdown of lipl-3 (A, B), and either sbp-1 (A, B) or fat-6/7 (C, D) abolished the increase in AS resistance seen in glp-1(ts) animals. (B, D) Data are represented as mean ± SEM. p < 0.05*; p < 0.01**; p < 0.001***. The interaction between glp-1(ts) and fat-6/7, lipl-3, sbp-1, and skn-1 were significant (p < 0.001). Additional information and statistics are provided in Table 2.DOI:http://dx.doi.org/10.7554/eLife.07836.018
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Related In: Results  -  Collection

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fig6s3: FA desaturation is required for GSC(−) stress resistance.glp-1(ts) and control day-1 adult worms treated with lipl-3, sbp-1, fat-6/7 mix, skn-1, or empty vector RNAi were exposed to 5 mM AS. Knockdown of lipl-3 (A, B), and either sbp-1 (A, B) or fat-6/7 (C, D) abolished the increase in AS resistance seen in glp-1(ts) animals. (B, D) Data are represented as mean ± SEM. p < 0.05*; p < 0.01**; p < 0.001***. The interaction between glp-1(ts) and fat-6/7, lipl-3, sbp-1, and skn-1 were significant (p < 0.001). Additional information and statistics are provided in Table 2.DOI:http://dx.doi.org/10.7554/eLife.07836.018
Mentions: We investigated whether accumulation of yolk-associated lipids might induce SKN-1 to mount a protective response. Supporting this idea, when the oocyte-specific yolk receptor rme-2 is knocked down, yolk accumulates to high levels (Grant and Hirsh, 1999), and in the intestine, SKN-1 accumulates in nuclei and its target gene gst-4 is activated (Figure 6C–F). Additionally, rme-2 RNAi increased stress resistance in a skn-1-dependent manner (Figure 6G and Table 2). When de novo lipogenesis was prevented by knockdown of the SREBP1 ortholog sbp-1 (Yang et al., 2006), SKN-1::GFP failed to accumulate in intestinal nuclei in response to GSC inhibition (Figure 6H,I), but not oxidative stress (Figure 6—figure supplement 2A) or reduced IIS (daf-2 mutants, Figure 6—figure supplement 2B). The sbp-1 lipogenesis defect can be rescued by supplementation with 600 µM OA (Yang et al., 2006), which is the most abundant FA in olive oil, chicken egg yolk, and human adipose tissue (National Research Council, 1976; Kokatnur et al., 1979). In C. elegans, the abundance of OA is increased in GSC(−) animals, and its synthesis by the FA desaturases, FAT-6 and FAT-7 (SCD orthologs), is required for GSC(−) lifespan extension (Goudeau et al., 2011). fat-6/7 were also required for SKN-1 to accumulate in nuclei after GSC inhibition (Figure 6J). Moreover, in GSC(−) animals subjected to sbp-1 RNAi, SKN-1 nuclear accumulation was fully restored by OA supplementation (Figure 6H,I). Consistent with their importance for SKN-1 function, sbp-1 and fat-6/7 were required for GSC absence to increase stress resistance (Figure 6—figure supplement 3).

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