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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

Enlarged VIT-2::GFP images.40× GFP and BF images of (A) GSC(+) and (B) GSC(−) animals are shown. Note that glp-1(ts);VIT-2::GFP is presented with 5× lower exposure times due to increased VIT-2::GFP intensity in GSC(−) animals. All worms shown are day-1 adults raised at 25°C. Arrowheads indicate the normal distribution of VIT-2::GFP in the intestine and oocytes, and arrows indicate the ectopic accumulation of VIT-2::GFP seen in GSC(−) animals. Numbers superimposed on images denote GFP exposure times.DOI:http://dx.doi.org/10.7554/eLife.07836.016
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fig6s1: Enlarged VIT-2::GFP images.40× GFP and BF images of (A) GSC(+) and (B) GSC(−) animals are shown. Note that glp-1(ts);VIT-2::GFP is presented with 5× lower exposure times due to increased VIT-2::GFP intensity in GSC(−) animals. All worms shown are day-1 adults raised at 25°C. Arrowheads indicate the normal distribution of VIT-2::GFP in the intestine and oocytes, and arrows indicate the ectopic accumulation of VIT-2::GFP seen in GSC(−) animals. Numbers superimposed on images denote GFP exposure times.DOI:http://dx.doi.org/10.7554/eLife.07836.016

Mentions: Given that SKN-1 inhibits fat storage, we considered whether the SKN-1 activation seen in GSC(−) animals might be triggered by lipid accumulation. It is possible that GSC loss simply increases production of certain fats. However, GSC ablation or inhibition prevents formation of oocytes, which endocytose lipid-rich yolk that is synthesized in the intestine (Grant and Hirsh, 1999). Fat storage might therefore be increased indirectly by GSC loss, through accumulation of unused yolk lipids. We tested a key prediction of this model by examining yolk accumulation and distribution, which can be visualized with GFP-tagged vitellogenin (YP170/VIT-2::GFP), a major yolk lipoprotein (Grant and Hirsh, 1999). VIT-2::GFP was visible primarily in oocytes and embryos in WT day-1 adults but accumulated to extremely high levels throughout the body cavity in the absence of GSCs (Figure 6A,B, and Figure 6—figure supplement 1). Apparently, yolk production was not slowed sufficiently to compensate for the lack of gametogenesis. The failure to consume yolk-associated lipid could account for the increase in overall fat storage seen in GSC(−) animals.10.7554/eLife.07836.015Figure 6.GSC absence activates SKN-1 through FA signaling.


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)

Enlarged VIT-2::GFP images.40× GFP and BF images of (A) GSC(+) and (B) GSC(−) animals are shown. Note that glp-1(ts);VIT-2::GFP is presented with 5× lower exposure times due to increased VIT-2::GFP intensity in GSC(−) animals. All worms shown are day-1 adults raised at 25°C. Arrowheads indicate the normal distribution of VIT-2::GFP in the intestine and oocytes, and arrows indicate the ectopic accumulation of VIT-2::GFP seen in GSC(−) animals. Numbers superimposed on images denote GFP exposure times.DOI:http://dx.doi.org/10.7554/eLife.07836.016
© Copyright Policy
Related In: Results  -  Collection

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

fig6s1: Enlarged VIT-2::GFP images.40× GFP and BF images of (A) GSC(+) and (B) GSC(−) animals are shown. Note that glp-1(ts);VIT-2::GFP is presented with 5× lower exposure times due to increased VIT-2::GFP intensity in GSC(−) animals. All worms shown are day-1 adults raised at 25°C. Arrowheads indicate the normal distribution of VIT-2::GFP in the intestine and oocytes, and arrows indicate the ectopic accumulation of VIT-2::GFP seen in GSC(−) animals. Numbers superimposed on images denote GFP exposure times.DOI:http://dx.doi.org/10.7554/eLife.07836.016
Mentions: Given that SKN-1 inhibits fat storage, we considered whether the SKN-1 activation seen in GSC(−) animals might be triggered by lipid accumulation. It is possible that GSC loss simply increases production of certain fats. However, GSC ablation or inhibition prevents formation of oocytes, which endocytose lipid-rich yolk that is synthesized in the intestine (Grant and Hirsh, 1999). Fat storage might therefore be increased indirectly by GSC loss, through accumulation of unused yolk lipids. We tested a key prediction of this model by examining yolk accumulation and distribution, which can be visualized with GFP-tagged vitellogenin (YP170/VIT-2::GFP), a major yolk lipoprotein (Grant and Hirsh, 1999). VIT-2::GFP was visible primarily in oocytes and embryos in WT day-1 adults but accumulated to extremely high levels throughout the body cavity in the absence of GSCs (Figure 6A,B, and Figure 6—figure supplement 1). Apparently, yolk production was not slowed sufficiently to compensate for the lack of gametogenesis. The failure to consume yolk-associated lipid could account for the increase in overall fat storage seen in GSC(−) animals.10.7554/eLife.07836.015Figure 6.GSC absence activates SKN-1 through FA signaling.

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