Limits...
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 regulation in the GSC longevity pathway.GSC absence results in activation of transcription factors in the intestine, with SKN-1 being regulated in parallel to DAF-12 and DAF-16. Yolk transport to oocytes is disrupted by GSC loss, resulting in lipid accumulation in the intestine and body cavity. The resulting SKN-1 activation requires OA, the FAT-6/7 FA desaturases, and the lysosomal lipases LIPL-1/3. This lipid-based signaling to SKN-1 depends partially upon LBP-8, which transports FAs from the lysosome to the nucleus. SKN-1 induces transcription of genes involved in stress resistance, detoxification, proteasome maintenance, extracellular matrix, and lipid metabolism, thereby reducing fat storage and increasing stress resistance and lifespan. Magenta denotes processes that are active in the presence of GSCs.DOI:http://dx.doi.org/10.7554/eLife.07836.019
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4541496&req=5

fig7: SKN-1 regulation in the GSC longevity pathway.GSC absence results in activation of transcription factors in the intestine, with SKN-1 being regulated in parallel to DAF-12 and DAF-16. Yolk transport to oocytes is disrupted by GSC loss, resulting in lipid accumulation in the intestine and body cavity. The resulting SKN-1 activation requires OA, the FAT-6/7 FA desaturases, and the lysosomal lipases LIPL-1/3. This lipid-based signaling to SKN-1 depends partially upon LBP-8, which transports FAs from the lysosome to the nucleus. SKN-1 induces transcription of genes involved in stress resistance, detoxification, proteasome maintenance, extracellular matrix, and lipid metabolism, thereby reducing fat storage and increasing stress resistance and lifespan. Magenta denotes processes that are active in the presence of GSCs.DOI:http://dx.doi.org/10.7554/eLife.07836.019

Mentions: By breaking down triglycerides, the lysosomal lipases LIPL-1/3 and LIPL-4 enable production of specific unsaturated FFAs that promote autophagy and longevity (Lapierre et al., 2011; O'Rourke et al., 2013; O'Rourke and Ruvkun, 2013; Folick et al., 2015). Some of these FAs are escorted from the lysosome to the nucleus by the conserved lipid-binding protein LBP-8/FABP1 (Folick et al., 2015; Han and Brunet, 2015). In GSC(−) animals, SKN-1 nuclear accumulation was inhibited modestly by lipl-4 RNAi but more strongly by lipl-1/3 double knockdown (Figure 6J). Furthermore, lipl-3 RNAi reduced stress resistance in GSC(−) but not WT animals (Figure 6—figure supplement 3A,B). Given that fat storage is increased in lipl-1/3 mutants (O'Rourke and Ruvkun, 2013), our data suggest that in GSC(−) animals, SKN-1 activity may depend upon particular lipl-1/3-dependent products, not lipid levels per se. Knockdown of lbp-8 or other LBPs also interfered with SKN-1::GFP nuclear accumulation in GSC(−) animals, and lbp-8 RNAi impaired SKN-1-dependent gst-4 activation by OA, indicating involvement of FA transport (Figure 6J,K). Together, our data suggest that in GSC(−) animals, excessive lipid levels lead to production of OA- and LIPL-1/3-dependent FAs that activate SKN-1, possibly through FA-based signaling (Figure 7).10.7554/eLife.07836.019Figure 7.SKN-1 regulation in the GSC longevity pathway.


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 regulation in the GSC longevity pathway.GSC absence results in activation of transcription factors in the intestine, with SKN-1 being regulated in parallel to DAF-12 and DAF-16. Yolk transport to oocytes is disrupted by GSC loss, resulting in lipid accumulation in the intestine and body cavity. The resulting SKN-1 activation requires OA, the FAT-6/7 FA desaturases, and the lysosomal lipases LIPL-1/3. This lipid-based signaling to SKN-1 depends partially upon LBP-8, which transports FAs from the lysosome to the nucleus. SKN-1 induces transcription of genes involved in stress resistance, detoxification, proteasome maintenance, extracellular matrix, and lipid metabolism, thereby reducing fat storage and increasing stress resistance and lifespan. Magenta denotes processes that are active in the presence of GSCs.DOI:http://dx.doi.org/10.7554/eLife.07836.019
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4541496&req=5

fig7: SKN-1 regulation in the GSC longevity pathway.GSC absence results in activation of transcription factors in the intestine, with SKN-1 being regulated in parallel to DAF-12 and DAF-16. Yolk transport to oocytes is disrupted by GSC loss, resulting in lipid accumulation in the intestine and body cavity. The resulting SKN-1 activation requires OA, the FAT-6/7 FA desaturases, and the lysosomal lipases LIPL-1/3. This lipid-based signaling to SKN-1 depends partially upon LBP-8, which transports FAs from the lysosome to the nucleus. SKN-1 induces transcription of genes involved in stress resistance, detoxification, proteasome maintenance, extracellular matrix, and lipid metabolism, thereby reducing fat storage and increasing stress resistance and lifespan. Magenta denotes processes that are active in the presence of GSCs.DOI:http://dx.doi.org/10.7554/eLife.07836.019
Mentions: By breaking down triglycerides, the lysosomal lipases LIPL-1/3 and LIPL-4 enable production of specific unsaturated FFAs that promote autophagy and longevity (Lapierre et al., 2011; O'Rourke et al., 2013; O'Rourke and Ruvkun, 2013; Folick et al., 2015). Some of these FAs are escorted from the lysosome to the nucleus by the conserved lipid-binding protein LBP-8/FABP1 (Folick et al., 2015; Han and Brunet, 2015). In GSC(−) animals, SKN-1 nuclear accumulation was inhibited modestly by lipl-4 RNAi but more strongly by lipl-1/3 double knockdown (Figure 6J). Furthermore, lipl-3 RNAi reduced stress resistance in GSC(−) but not WT animals (Figure 6—figure supplement 3A,B). Given that fat storage is increased in lipl-1/3 mutants (O'Rourke and Ruvkun, 2013), our data suggest that in GSC(−) animals, SKN-1 activity may depend upon particular lipl-1/3-dependent products, not lipid levels per se. Knockdown of lbp-8 or other LBPs also interfered with SKN-1::GFP nuclear accumulation in GSC(−) animals, and lbp-8 RNAi impaired SKN-1-dependent gst-4 activation by OA, indicating involvement of FA transport (Figure 6J,K). Together, our data suggest that in GSC(−) animals, excessive lipid levels lead to production of OA- and LIPL-1/3-dependent FAs that activate SKN-1, possibly through FA-based signaling (Figure 7).10.7554/eLife.07836.019Figure 7.SKN-1 regulation in the GSC longevity pathway.

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