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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 promotes longevity and stress resistance in germline stem cell (GSC)(−) animals.(A, B) Wild type, skn-1(zu135), glp-1(bn18ts), and glp-1(bn18ts);skn-1(zu135) double mutants were assayed for lifespan at 25°C. skn-1(zu135) is a presumed  that is used throughout the study. Unless otherwise specified, glp-1(ts) refers to glp-1(bn18ts). (A) Composite survival curve. (B) Graph of mean lifespans. (C–F) glp-1(ts) mutants require skn-1 for oxidative stress resistance. Day-3 adult glp-1(ts) and control worms treated with skn-1 RNAi or empty vector were exposed to (C, D) 5 mM sodium arsenite (AS) or (E, F) 15.4 mM tert-butyl hydroperoxide (TBHP). Data are represented as mean ± SEM. p < 0.001***. The interaction between glp-1 and skn-1 was significant for both lifespan and stress resistance (p < 0.001). Statistical analysis and replicates are in Tables 1, 2.DOI:http://dx.doi.org/10.7554/eLife.07836.003
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fig1: SKN-1 promotes longevity and stress resistance in germline stem cell (GSC)(−) animals.(A, B) Wild type, skn-1(zu135), glp-1(bn18ts), and glp-1(bn18ts);skn-1(zu135) double mutants were assayed for lifespan at 25°C. skn-1(zu135) is a presumed that is used throughout the study. Unless otherwise specified, glp-1(ts) refers to glp-1(bn18ts). (A) Composite survival curve. (B) Graph of mean lifespans. (C–F) glp-1(ts) mutants require skn-1 for oxidative stress resistance. Day-3 adult glp-1(ts) and control worms treated with skn-1 RNAi or empty vector were exposed to (C, D) 5 mM sodium arsenite (AS) or (E, F) 15.4 mM tert-butyl hydroperoxide (TBHP). Data are represented as mean ± SEM. p < 0.001***. The interaction between glp-1 and skn-1 was significant for both lifespan and stress resistance (p < 0.001). Statistical analysis and replicates are in Tables 1, 2.DOI:http://dx.doi.org/10.7554/eLife.07836.003

Mentions: To investigate the importance of skn-1 in GSC(−) animals, we analyzed temperature-sensitive (ts) mutations in glp-1/Notch, which is required for GSC proliferation (Kimble and Crittenden, 2005). glp-1(ts) mutants that undergo larval development at the non-permissive temperature of 25°C (GSC(−) animals) are sterile, exhibit a markedly reduced number of GSCs, and live considerably longer than wild type (WT) controls (Arantes-Oliveira et al., 2002) (Figure 1A,B). By contrast, this lifespan extension was blocked in a skn-1 mutant background (Figure 1A,B). Lack of skn-1 also impaired lifespan extension when glp-1(ts) animals were downshifted to 20°C after development was complete (Table 1). Similar results were obtained with or without 5-fluoro-2′-deoxyuridine (FUdR), which inhibits offspring formation in the control (Table 1). Consistent with these findings, in an earlier experiment in which glp-1(ts) extended lifespan by less than 7%, skn-1 knockdown by RNA interference (RNAi) prevented this increase (Vilchez et al., 2012). In contrast to daf-16, skn-1 was also required for GSC inhibition to increase oxidative stress resistance (Figure 1C–F; Table 2).10.7554/eLife.07836.003Figure 1.SKN-1 promotes longevity and stress resistance in germline stem cell (GSC)(−) animals.


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 promotes longevity and stress resistance in germline stem cell (GSC)(−) animals.(A, B) Wild type, skn-1(zu135), glp-1(bn18ts), and glp-1(bn18ts);skn-1(zu135) double mutants were assayed for lifespan at 25°C. skn-1(zu135) is a presumed  that is used throughout the study. Unless otherwise specified, glp-1(ts) refers to glp-1(bn18ts). (A) Composite survival curve. (B) Graph of mean lifespans. (C–F) glp-1(ts) mutants require skn-1 for oxidative stress resistance. Day-3 adult glp-1(ts) and control worms treated with skn-1 RNAi or empty vector were exposed to (C, D) 5 mM sodium arsenite (AS) or (E, F) 15.4 mM tert-butyl hydroperoxide (TBHP). Data are represented as mean ± SEM. p < 0.001***. The interaction between glp-1 and skn-1 was significant for both lifespan and stress resistance (p < 0.001). Statistical analysis and replicates are in Tables 1, 2.DOI:http://dx.doi.org/10.7554/eLife.07836.003
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4541496&req=5

fig1: SKN-1 promotes longevity and stress resistance in germline stem cell (GSC)(−) animals.(A, B) Wild type, skn-1(zu135), glp-1(bn18ts), and glp-1(bn18ts);skn-1(zu135) double mutants were assayed for lifespan at 25°C. skn-1(zu135) is a presumed that is used throughout the study. Unless otherwise specified, glp-1(ts) refers to glp-1(bn18ts). (A) Composite survival curve. (B) Graph of mean lifespans. (C–F) glp-1(ts) mutants require skn-1 for oxidative stress resistance. Day-3 adult glp-1(ts) and control worms treated with skn-1 RNAi or empty vector were exposed to (C, D) 5 mM sodium arsenite (AS) or (E, F) 15.4 mM tert-butyl hydroperoxide (TBHP). Data are represented as mean ± SEM. p < 0.001***. The interaction between glp-1 and skn-1 was significant for both lifespan and stress resistance (p < 0.001). Statistical analysis and replicates are in Tables 1, 2.DOI:http://dx.doi.org/10.7554/eLife.07836.003
Mentions: To investigate the importance of skn-1 in GSC(−) animals, we analyzed temperature-sensitive (ts) mutations in glp-1/Notch, which is required for GSC proliferation (Kimble and Crittenden, 2005). glp-1(ts) mutants that undergo larval development at the non-permissive temperature of 25°C (GSC(−) animals) are sterile, exhibit a markedly reduced number of GSCs, and live considerably longer than wild type (WT) controls (Arantes-Oliveira et al., 2002) (Figure 1A,B). By contrast, this lifespan extension was blocked in a skn-1 mutant background (Figure 1A,B). Lack of skn-1 also impaired lifespan extension when glp-1(ts) animals were downshifted to 20°C after development was complete (Table 1). Similar results were obtained with or without 5-fluoro-2′-deoxyuridine (FUdR), which inhibits offspring formation in the control (Table 1). Consistent with these findings, in an earlier experiment in which glp-1(ts) extended lifespan by less than 7%, skn-1 knockdown by RNA interference (RNAi) prevented this increase (Vilchez et al., 2012). In contrast to daf-16, skn-1 was also required for GSC inhibition to increase oxidative stress resistance (Figure 1C–F; Table 2).10.7554/eLife.07836.003Figure 1.SKN-1 promotes longevity and stress resistance in germline stem cell (GSC)(−) animals.

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