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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

RNA-seq counts of select lipid metabolism and yolk transporter genes.Expression of the known SKN-1 target genes gst-4 and nit-1 is elevated in GSC(−) animals in a skn-1-dependent manner. The TAG lipase lipl-3 and FABP lbp-8 are similarly elevated in GSC(−) animals in a skn-1-dependent manner, but expression of sbp-1, dhs-3, and yolk protein vitellogenins (VIT genes) are not affected by skn-1 RNAi. rme-2 expression is germline enriched but regulated independently of skn-1. Open circles denote replicates. Vertical lines indicate mean counts per million (CPM).DOI:http://dx.doi.org/10.7554/eLife.07836.014
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fig5s3: RNA-seq counts of select lipid metabolism and yolk transporter genes.Expression of the known SKN-1 target genes gst-4 and nit-1 is elevated in GSC(−) animals in a skn-1-dependent manner. The TAG lipase lipl-3 and FABP lbp-8 are similarly elevated in GSC(−) animals in a skn-1-dependent manner, but expression of sbp-1, dhs-3, and yolk protein vitellogenins (VIT genes) are not affected by skn-1 RNAi. rme-2 expression is germline enriched but regulated independently of skn-1. Open circles denote replicates. Vertical lines indicate mean counts per million (CPM).DOI:http://dx.doi.org/10.7554/eLife.07836.014

Mentions: Several lines of evidence support this model. GSC inhibition induces SKN-1 and NHR-49 to upregulate largely distinct sets of FA oxidation genes (Figure 5A) (Ratnappan et al., 2014). This effect of SKN-1 could account for its inhibitory role in fat accumulation (Figure 5B,C). A need to metabolize excess fat could also explain the importance of lipophagy in GSC(−) longevity (Lapierre et al., 2011; Hansen et al., 2013). With respect to signaling lipids, GSC(−) longevity requires the triglyceride lipase LIPL-4 (Wang et al., 2008), which generates unsaturated FFAs that promote longevity (O'Rourke et al., 2013; Folick et al., 2015). While LIPL-4-dependent FAs act through NHR-49 and NHR-80 (Lapierre et al., 2011; Folick et al., 2015), and possibly not SKN-1 (Figure 6J), in GSC(−) animals, SKN-1 activation involves the LIPL-1/3 lipases (Figure 6J), which also promote longevity (O'Rourke and Ruvkun, 2013). This elevated SKN-1 activity also depends upon lipid transfer proteins, as well as OA (Figure 6H–J and Figure 6—figure supplement 1C). OA is required for GSC(−) longevity (Goudeau et al., 2011) and is a precursor to unsaturated FAs that have signaling functions (O'Rourke et al., 2013; Folick et al., 2015). Finally, SKN-1 upregulates lipl-3 and lbp-8 in WT and GSC(−) animals (Figure 5A and Figure 5—figure supplement 3; Supplementary file 1a,c), suggesting that it may function both downstream and upstream of lipid signals. The idea that SKN-1 can be activated by lipids that arise from prevention of reproduction and yolk consumption should be considered in evaluation of genetic or pharmacological interventions that increase SKN-1 activity.


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)

RNA-seq counts of select lipid metabolism and yolk transporter genes.Expression of the known SKN-1 target genes gst-4 and nit-1 is elevated in GSC(−) animals in a skn-1-dependent manner. The TAG lipase lipl-3 and FABP lbp-8 are similarly elevated in GSC(−) animals in a skn-1-dependent manner, but expression of sbp-1, dhs-3, and yolk protein vitellogenins (VIT genes) are not affected by skn-1 RNAi. rme-2 expression is germline enriched but regulated independently of skn-1. Open circles denote replicates. Vertical lines indicate mean counts per million (CPM).DOI:http://dx.doi.org/10.7554/eLife.07836.014
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4541496&req=5

fig5s3: RNA-seq counts of select lipid metabolism and yolk transporter genes.Expression of the known SKN-1 target genes gst-4 and nit-1 is elevated in GSC(−) animals in a skn-1-dependent manner. The TAG lipase lipl-3 and FABP lbp-8 are similarly elevated in GSC(−) animals in a skn-1-dependent manner, but expression of sbp-1, dhs-3, and yolk protein vitellogenins (VIT genes) are not affected by skn-1 RNAi. rme-2 expression is germline enriched but regulated independently of skn-1. Open circles denote replicates. Vertical lines indicate mean counts per million (CPM).DOI:http://dx.doi.org/10.7554/eLife.07836.014
Mentions: Several lines of evidence support this model. GSC inhibition induces SKN-1 and NHR-49 to upregulate largely distinct sets of FA oxidation genes (Figure 5A) (Ratnappan et al., 2014). This effect of SKN-1 could account for its inhibitory role in fat accumulation (Figure 5B,C). A need to metabolize excess fat could also explain the importance of lipophagy in GSC(−) longevity (Lapierre et al., 2011; Hansen et al., 2013). With respect to signaling lipids, GSC(−) longevity requires the triglyceride lipase LIPL-4 (Wang et al., 2008), which generates unsaturated FFAs that promote longevity (O'Rourke et al., 2013; Folick et al., 2015). While LIPL-4-dependent FAs act through NHR-49 and NHR-80 (Lapierre et al., 2011; Folick et al., 2015), and possibly not SKN-1 (Figure 6J), in GSC(−) animals, SKN-1 activation involves the LIPL-1/3 lipases (Figure 6J), which also promote longevity (O'Rourke and Ruvkun, 2013). This elevated SKN-1 activity also depends upon lipid transfer proteins, as well as OA (Figure 6H–J and Figure 6—figure supplement 1C). OA is required for GSC(−) longevity (Goudeau et al., 2011) and is a precursor to unsaturated FAs that have signaling functions (O'Rourke et al., 2013; Folick et al., 2015). Finally, SKN-1 upregulates lipl-3 and lbp-8 in WT and GSC(−) animals (Figure 5A and Figure 5—figure supplement 3; Supplementary file 1a,c), suggesting that it may function both downstream and upstream of lipid signals. The idea that SKN-1 can be activated by lipids that arise from prevention of reproduction and yolk consumption should be considered in evaluation of genetic or pharmacological interventions that increase SKN-1 activity.

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