Terma
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- May 8, 2017
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@Amazoniac: Follow-up to Anti-Peat - Grant Genereux's Theory Of Vitamin A Toxicity
Rhythmic Diurnal Synthesis and Signaling of Retinoic Acid in the Rat Pineal Gland and Its Action to Rapidly Downregulate ERK Phosphorylation
So I had to tweak my thoughts on the circadian nature of retinoic acid. Although it is tied to food consumption through the environmental and visual cue of carotenoids, RA synthesis (RALDH) mostly seems to serves as a morning signal and should be interacting with light cues (combined with CLOCK/BMAL1). It is less about RA being high all day or in response to food (which might not happen as dramatically in healthy circumstances) and more about it hitting a peak in the late night/morning. This makes sense after all since in organs like the liver NAD+/NADH ratio required for RALDH is highest in the morning with high levels before waking (as the electrons are expected to be lowered - for one - after having been donated to fuel skeletal growth/restructuring).
This would make sense as a way to counteract the growth-hormone-ablated GNMT expression that serves to increase methyl group availability during the night; something has to counteract this. RA stops methylation, restores the transsulfuration pathway and we begin the day. CYP26 may be especially relevant to help restrain the RA increase, with an input from NADPH availability (which may affect timing of breakdown), but I'm not sure exactly what shape it gives the curve.
More importantly: RA would promote the processes of differentiation at the end of the night, after growth hormone did its work. It completes the nighttime processes. GH has a limited window to work at the start of the night using the nutrients acquired during the day.
This could also explain another reason why RA has the potential to increase cortisol (see various studies on its HPA axis effects - despite the doses): it helps propel the "stop healing, wake up" signal, or the transition from sleep/growth to wake.
At the same time, SIRT1 increases in organs like the liver in the morning due to the higher NAD+/NADH ratio - and it's known that RAR and SIRT1 interact:
Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells
SIRT1 seems to antagonize RAR; I imagine SIRT1 and RALDH (retinaldehyde->RA) may compete for NAD+ availability or there may be a transcription effect.
I'm not 100% sure about this and it's not essential to understand, but you can almost piece it together:
http://www.jbc.org/content/287/50/42195.full.pdf
SIRT1 seems to increase when differentiation goes from RAR (early) and progresses to PPARdelta (which increases fatty acid utilization for differentiation). I'm not sure about the causality but it seems like PPARdelta and SIRT1 function to help finish differentiation.
Finally, from the original article (they put all their focus on this in the abstract), after 48 hours RA modulates melatonin release through being lowered at the start of the night and increasing toward the end, seemingly by increasing AANAT mRNA at those times and maintaining rhythmicity (not totally clear).
I'll probably have to tweak this again, but from this view it starts to make a lot more sense as it gives RA at least one clear role and timeframe, though there could be organ-specific differences. Of course carotenoids are an important environmental and visual cue for nutrient abundance for mammals, so they should tie into this as well. At the same time you can imagine all the ways this might go wrong, because cellular differentiation is not a simple process and it needs to be timed, much like everything about sleep.
There could be some misinterpretations in this - because RA circadian studies are some of the most complicated I've ever read, and there are likely to be organ-specific difference, and rats/mice vs humans adds extra layers of confusion/complexity in circadian studies - but I'm getting a little more confident as time goes on that it's something along these lines.
Rhythmic Diurnal Synthesis and Signaling of Retinoic Acid in the Rat Pineal Gland and Its Action to Rapidly Downregulate ERK Phosphorylation
Vitamin A is important for the circadian timing system; deficiency disrupts daily rhythms in activity and clock gene expression, and reduces the nocturnal peak in melatonin in the pineal gland. However, it is currently unknown how these effects are mediated. Vitamin A primarily acts via the active metabolite, retinoic acid (RA), a transcriptional regulator with emerging non-genomic activities. We investigated whether RA is subject to diurnal variation in synthesis and signaling in the rat pineal gland. Its involvement in two key molecular rhythms in this gland was also examined: kinase activation and induction of Aanat, which encodes the rhythm-generating melatonin synthetic enzyme. We found diurnal changes in expression of several genes required for RA signaling, including a RA receptor and synthetic enzymes. The RA-responsive gene Cyp26a1 was found to change between day and night, suggesting diurnal changes in RA activity. This corresponded to changes in RA synthesis, suggesting rhythmic production of RA. Long-term RA treatment in vitro upregulated Aanat transcription, while short-term treatment had no effect. RA was also found to rapidly downregulate extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, suggesting a rapid non-genomic action which may be involved in driving the molecular rhythm in ERK1/2 activation in this gland. These results demonstrate that there are diurnal changes in RA synthesis and activity in the rat pineal gland which are partially under circadian control. These may be key to the effects of vitamin A on circadian rhythms, therefore providing insight into the molecular link between this nutrient and the circadian system.
So I had to tweak my thoughts on the circadian nature of retinoic acid. Although it is tied to food consumption through the environmental and visual cue of carotenoids, RA synthesis (RALDH) mostly seems to serves as a morning signal and should be interacting with light cues (combined with CLOCK/BMAL1). It is less about RA being high all day or in response to food (which might not happen as dramatically in healthy circumstances) and more about it hitting a peak in the late night/morning. This makes sense after all since in organs like the liver NAD+/NADH ratio required for RALDH is highest in the morning with high levels before waking (as the electrons are expected to be lowered - for one - after having been donated to fuel skeletal growth/restructuring).
This would make sense as a way to counteract the growth-hormone-ablated GNMT expression that serves to increase methyl group availability during the night; something has to counteract this. RA stops methylation, restores the transsulfuration pathway and we begin the day. CYP26 may be especially relevant to help restrain the RA increase, with an input from NADPH availability (which may affect timing of breakdown), but I'm not sure exactly what shape it gives the curve.
More importantly: RA would promote the processes of differentiation at the end of the night, after growth hormone did its work. It completes the nighttime processes. GH has a limited window to work at the start of the night using the nutrients acquired during the day.
This could also explain another reason why RA has the potential to increase cortisol (see various studies on its HPA axis effects - despite the doses): it helps propel the "stop healing, wake up" signal, or the transition from sleep/growth to wake.
At the same time, SIRT1 increases in organs like the liver in the morning due to the higher NAD+/NADH ratio - and it's known that RAR and SIRT1 interact:
Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells
SIRT1 seems to antagonize RAR; I imagine SIRT1 and RALDH (retinaldehyde->RA) may compete for NAD+ availability or there may be a transcription effect.
I'm not 100% sure about this and it's not essential to understand, but you can almost piece it together:
http://www.jbc.org/content/287/50/42195.full.pdf
SIRT1 seems to increase when differentiation goes from RAR (early) and progresses to PPARdelta (which increases fatty acid utilization for differentiation). I'm not sure about the causality but it seems like PPARdelta and SIRT1 function to help finish differentiation.
Finally, from the original article (they put all their focus on this in the abstract), after 48 hours RA modulates melatonin release through being lowered at the start of the night and increasing toward the end, seemingly by increasing AANAT mRNA at those times and maintaining rhythmicity (not totally clear).
I'll probably have to tweak this again, but from this view it starts to make a lot more sense as it gives RA at least one clear role and timeframe, though there could be organ-specific differences. Of course carotenoids are an important environmental and visual cue for nutrient abundance for mammals, so they should tie into this as well. At the same time you can imagine all the ways this might go wrong, because cellular differentiation is not a simple process and it needs to be timed, much like everything about sleep.
There could be some misinterpretations in this - because RA circadian studies are some of the most complicated I've ever read, and there are likely to be organ-specific difference, and rats/mice vs humans adds extra layers of confusion/complexity in circadian studies - but I'm getting a little more confident as time goes on that it's something along these lines.