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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

SKN-1 is activated in response to FA signaling.Accumulation of SKN-1 in intestinal nuclei in (A) response to arsenite exposure for 30 min or (B) daf-2 mutants is not impaired by sbp-1 RNAi. (C) Effects of OA and CO doses on intestinal gst-4p::GFP expression, compared to AS treatment. (D) Larval development and (E) egg laying rate are not affected by OA or CO treatment. CO supplementation induces intestinal (F) SKN-1 nuclear accumulation but not (G) DAF-16 accumulation. (H, I) DAF-16 accumulation in glp-1(e2141ts) is unaffected by sbp-1 RNAi. (H) Representative 40× DIC images of day-1 adults. (J) PMK-1 (p38 kinase) phosphorylation is not affected by GSC removal, consistent with a previous report (Alper et al., 2010). PMK-1 phosphorylation is increased dramatically by AS oxidative stress and reflects activation of its kinase activity (Inoue et al., 2005). (A–C, F, G, I) GFP quantification with high, medium, low scoring. Numbers above bars denote sample size. p < 0.05*; p < 0.01**; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.017
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fig6s2: SKN-1 is activated in response to FA signaling.Accumulation of SKN-1 in intestinal nuclei in (A) response to arsenite exposure for 30 min or (B) daf-2 mutants is not impaired by sbp-1 RNAi. (C) Effects of OA and CO doses on intestinal gst-4p::GFP expression, compared to AS treatment. (D) Larval development and (E) egg laying rate are not affected by OA or CO treatment. CO supplementation induces intestinal (F) SKN-1 nuclear accumulation but not (G) DAF-16 accumulation. (H, I) DAF-16 accumulation in glp-1(e2141ts) is unaffected by sbp-1 RNAi. (H) Representative 40× DIC images of day-1 adults. (J) PMK-1 (p38 kinase) phosphorylation is not affected by GSC removal, consistent with a previous report (Alper et al., 2010). PMK-1 phosphorylation is increased dramatically by AS oxidative stress and reflects activation of its kinase activity (Inoue et al., 2005). (A–C, F, G, I) GFP quantification with high, medium, low scoring. Numbers above bars denote sample size. p < 0.05*; p < 0.01**; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.017

Mentions: (A) Accumulation of yolk transporter VIT-2::GFP in the soma of GSC(−) animals. Detailed higher magnification images are provided in Figure 6—figure supplement 1. (B) COPAS quantification of VIT-2::GFP. Data are represented as mean ± SEM. (C) Knockdown of the oocyte-specific yolk receptor rme-2 promotes somatic VIT-2 accumulation. (D–F) rme-2 RNAi activates SKN-1 in the intestine. (D, E) SKN-1::GFP accumulates in intestinal nuclei in rme-2 RNAi-treated worms. (F) In rme-2 RNAi-treated worms, gst-4p::GFP levels in the intestine are increased at the L4 stage and increased further by day-1 adulthood. (G) rme-2 RNAi enhances resistance to AS, in a skn-1-dependent manner (see replicates in Table 2). (H, I) An oleic acid (OA)-dependent signal is required for SKN-1 to be activated by GSC inhibition but not oxidative stress. In GSC(−) animals, SKN-1 nuclear accumulation is abolished by sbp-1 RNAi and rescued by OA supplementation. SKN-1 remains capable of responding to oxidative stress (30 min AS exposure) after sbp-1 RNAi in GSC(−) (H, I) or WT (Figure 6—figure supplement 2A) worms. (J) Dependence of SKN-1::GFP accumulation in GSC(−) animals on FAT-6/7-mediated FA desaturation, and proteins that generate free unsaturated FAs (LIPL-1/-3 lipases), or transport them to the nucleus (LBP-6/7/8). (K) OA and coconut oil (CO) increase skn-1-dependent gst-4p::GFP expression in the intestine. lbp-8 RNAi reduces induction by OA. (A, C) Representative 10× GFP images. (D, H) Representative 40× GFP images of day-1 adults. (E, F, I–K) GFP quantification with high, medium, low scoring. 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)

SKN-1 is activated in response to FA signaling.Accumulation of SKN-1 in intestinal nuclei in (A) response to arsenite exposure for 30 min or (B) daf-2 mutants is not impaired by sbp-1 RNAi. (C) Effects of OA and CO doses on intestinal gst-4p::GFP expression, compared to AS treatment. (D) Larval development and (E) egg laying rate are not affected by OA or CO treatment. CO supplementation induces intestinal (F) SKN-1 nuclear accumulation but not (G) DAF-16 accumulation. (H, I) DAF-16 accumulation in glp-1(e2141ts) is unaffected by sbp-1 RNAi. (H) Representative 40× DIC images of day-1 adults. (J) PMK-1 (p38 kinase) phosphorylation is not affected by GSC removal, consistent with a previous report (Alper et al., 2010). PMK-1 phosphorylation is increased dramatically by AS oxidative stress and reflects activation of its kinase activity (Inoue et al., 2005). (A–C, F, G, I) GFP quantification with high, medium, low scoring. Numbers above bars denote sample size. p < 0.05*; p < 0.01**; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.017
© Copyright Policy
Related In: Results  -  Collection

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fig6s2: SKN-1 is activated in response to FA signaling.Accumulation of SKN-1 in intestinal nuclei in (A) response to arsenite exposure for 30 min or (B) daf-2 mutants is not impaired by sbp-1 RNAi. (C) Effects of OA and CO doses on intestinal gst-4p::GFP expression, compared to AS treatment. (D) Larval development and (E) egg laying rate are not affected by OA or CO treatment. CO supplementation induces intestinal (F) SKN-1 nuclear accumulation but not (G) DAF-16 accumulation. (H, I) DAF-16 accumulation in glp-1(e2141ts) is unaffected by sbp-1 RNAi. (H) Representative 40× DIC images of day-1 adults. (J) PMK-1 (p38 kinase) phosphorylation is not affected by GSC removal, consistent with a previous report (Alper et al., 2010). PMK-1 phosphorylation is increased dramatically by AS oxidative stress and reflects activation of its kinase activity (Inoue et al., 2005). (A–C, F, G, I) GFP quantification with high, medium, low scoring. Numbers above bars denote sample size. p < 0.05*; p < 0.01**; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.017
Mentions: (A) Accumulation of yolk transporter VIT-2::GFP in the soma of GSC(−) animals. Detailed higher magnification images are provided in Figure 6—figure supplement 1. (B) COPAS quantification of VIT-2::GFP. Data are represented as mean ± SEM. (C) Knockdown of the oocyte-specific yolk receptor rme-2 promotes somatic VIT-2 accumulation. (D–F) rme-2 RNAi activates SKN-1 in the intestine. (D, E) SKN-1::GFP accumulates in intestinal nuclei in rme-2 RNAi-treated worms. (F) In rme-2 RNAi-treated worms, gst-4p::GFP levels in the intestine are increased at the L4 stage and increased further by day-1 adulthood. (G) rme-2 RNAi enhances resistance to AS, in a skn-1-dependent manner (see replicates in Table 2). (H, I) An oleic acid (OA)-dependent signal is required for SKN-1 to be activated by GSC inhibition but not oxidative stress. In GSC(−) animals, SKN-1 nuclear accumulation is abolished by sbp-1 RNAi and rescued by OA supplementation. SKN-1 remains capable of responding to oxidative stress (30 min AS exposure) after sbp-1 RNAi in GSC(−) (H, I) or WT (Figure 6—figure supplement 2A) worms. (J) Dependence of SKN-1::GFP accumulation in GSC(−) animals on FAT-6/7-mediated FA desaturation, and proteins that generate free unsaturated FAs (LIPL-1/-3 lipases), or transport them to the nucleus (LBP-6/7/8). (K) OA and coconut oil (CO) increase skn-1-dependent gst-4p::GFP expression in the intestine. lbp-8 RNAi reduces induction by OA. (A, C) Representative 10× GFP images. (D, H) Representative 40× GFP images of day-1 adults. (E, F, I–K) GFP quantification with high, medium, low scoring. 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