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What if the so-called RXR (Vitamin A receptor) was improperly named?

People say, "if we aren't supposed to have Vitamin A, why do we have receptors for it?"
 

I have an answer that raises more questions...just because something activates a receptor, it absolutely does not mean that the receptor's main purpose is for that compound. Just because we can put something in our mouth and swallow it, doesn't mean it is "food", right?

The Retinoid X Receptors and Their Ligands

The natural ligand of RXR remains controversial. Although 9-cis-retinoic acid (9-cis-RA in Fig. 1A) was first proposed to have this status, many groups have since been unable to detect endogenous 9-cis-RA in cells either in culture or in vivo unless its isomer, all-transretinoic acid (ATRA), had been present first or added [1,2]. Compounding the uncertainty of its status as the natural ligand of RXR is the instability of the RA tetraene side chain that either in the presence of light or a mercaptan, such as reduced glutathione, can equilibrate to a mixture of double-bond isomers generally containing 80% ATRA, 8–10% 9-cis-RA, and other isomers.

The first sentence translated to normal terms:

  • "ligand" = a molecule that binds to another (usually larger) molecule
  • "RXR" = retinoic acid [aka oxidized form of Vitamin A] receptor
  • "controversial" = giving rise or likely to give rise to disagreement

Are there other ligands of the so-called RXR? Yes! Why wasn't it named after those instead, one should ask...from the same paper:

Polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and a saturated metabolite of chlorophyll, phytanic acid (Fig. 1A), were also identified as RXR ligands.

The following paper says that 9-cis-retinoic acid is NOT the endogenous ligand for the RXR!

Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor?

Specific proteins in the nucleus act as transcription factors upon activation through binding of small molecules (all-trans-retinoic acid, thyroid hormone, vitamin D, and others). The activated (liganded) receptors bind to specific DNA elements as heterodimers, each in combination with the retinoic acid-X receptor (RXR). 9-Cis-retinoic acid binds to RXR with high affinity and activates it. Though 9-cis-retinoic acid was initially found in animal tissues, in later work 9-cis-retinoic acid could not be detected. A search for a ligand for RXR in tissues showed that unsaturated fatty acids, particularly linoleic, linolenic, and docosahexaenoic acids, bound to and activated RXR as specific ligands, although with low affinity. A critical experiment demonstrated that, at least in developing mouse skin, 9-cis-retinoic acid is not the ligand for RXR.

9-cis-retinoic acid is not the natural ligand for RXR...REPEAT...9-cis-retinoic acid is NOT the natural ligand for RXR. Would you like another paper that says the same thing, in a different way?

Polyunsaturated Fatty Acids Including Docosahexaenoic and Arachidonic Acid Bind to the Retinoid X Receptor α Ligand-binding Domain

Although 9-cis-RA has been described as the natural ligand for RXR (6), it has been difficult to detect in vivo (812). However, recently presented evidence indicates that RXR can also become activated by naturally occurring polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) (13). Significantly, whereas 9-cis-RA is difficult to detect in vivo, DHA is abundant in the postnatal brain, making it a prime candidate as a natural ligand for RXR (reviewed in Refs. 14 and 15).

More on DHA being an endogenous ligand for the RXR:

Docosahexaenoic Acid, a Ligand for the Retinoid X Receptor in Mouse Brain

The retinoid X receptor (RXR) is a nuclear receptor that functions as a ligand-activated transcription factor. Little is known about the ligands that activate RXR in vivo. Here, we identified a factor in brain tissue from adult mice that activates RXR in cell-based assays. Purification and analysis of the factor by mass spectrometry revealed that it is docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid that is highly enriched in the adult mammalian brain. Previous work has shown that DHA is essential for brain maturation, and deficiency of DHA in both rodents and humans leads to impaired spatial learning and other abnormalities. These data suggest that DHA may influence neural function through activation of an RXR signaling pathway.

Omega-3 polyunsaturated fatty acids reverse age-related decreases in retinoic acid receptors, retinoid x receptors and peroxisome-proliferator-activated receptors in rat forebrain

Omega-3 polyunsaturated fatty acids reverse age-related decreases in retinoic acid receptors, retinoid x receptors and peroxisome-proliferator-activated receptors in rat forebrain
So docosahexanoic acid (DHA) and eicosapentanoic acid (EPA), known ESSENTIAL components of the brain, were able to fully reverse the age-related changes in the so-called "Retinoic Acid Receptors"?  Note that it is specifically stated that EPA and DHA actually ARE endogenous ligands for the RXR! Is it pretty clear yet that the RAR, RXR, Vitamin A Receptor, or whatever you want to call it, is INCORRECTLY NAMED?
It seems pretty straightforward and backs the concept that Poison/"Vitamin A" is NOT the essential nutrient that everyone thinks it is...it is a toxin that binds to a receptor, an impostor. NOTE:  I am not advocating taking supplemental DHA and/or EPA based on the above.  In my Nutritional Restoration programs, and with people picking properly-fed animal proteins, I don't believe supplementing them is necessary or wise. We simply need to remove the retinoic acids that block their activity.
Some out there try to completely justify using supplemental forms of Vitamin A (including cod liver oil) simply because they can find research on the receptor named "RXR". With some deeper digging and a deeper understanding, we see that things are not that simple, and the common understanding has great potential to be completely WRONG.
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Dr. Garrett Smith, the "Nutrition Detective"
Licensed Naturopathic Physician (NMD) in Arizona
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DHA (an omega-3) is a fatty acid, ether-soluble, and present in butterfat, and is a natural ligand for the RXR. It is also used as a treatment for xerophthalmia, and blindness has occurred in children who have disorders of DHA metabolism.
Arachidonic acid (an omega-6) is a fatty acid, I don't know its solubility in ether, and is also present in butterfat, and is another ligand for the RXR.
It would seem that both of these nutrients are important to the proper development of the eye's functions:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848685/
Dr. Garrett Smith, the "Nutrition Detective"
Licensed Naturopathic Physician (NMD) in Arizona
Interested in my comprehensive Poison/"Vitamin A" Detox program? Contact Us
Want to work directly with me? I work with US and International clients! Contact my office
Enjoy seeing this work? Want to see more of it? Donations gratefully accepted! Click Here
If you order from iHerb, use my affiliate coupon code NCJ477 to get 5% Off!
If you order from Amazon, here is the Nutrition Restored Amazon Product List.
FaceBook Notes (aka my "blogging" for a long time)
My YouTube Channel
The goal is to eventually move everything to this website, as social media is without a doubt a great poison to humanity.
Medical Disclaimer