I needed to disable self sign-ups because I’ve been getting too many spam-type accounts. Thanks.
Individuals deficient in RBP develop VAD symptoms
RBP4
Until recently, research concerning retinoid transport has focused almost solely on retinol-RBP4 (53). Twenty years ago, it would have been predicted by most researchers that individuals lacking RBP4 would not be found since the absence of RBP4 would likely result in death at a very early age due to impairments to essential retinoid-dependent functions, like the maintenance of immunity and barrier function. However, research undertaken in the last fifteen years, both basic and clinical research, has demonstrated that other pathways for retinoid transport are also physiologically important. This idea is best evidenced in the existence of humans who completely lack RBP4 and are thus RBP4-deficient. These individuals display impaired vision and in some instances ocular defects, but do not exhibit other more severe signs of retinoid deficiency. In 1999, two female siblings living in Germany, with a known history of night blindness and slightly reduced visual acuity, were admitted to the hospital and found to have undetectable plasma RBP4 concentrations (<0.6 µM) and extremely low plasma retinol concentrations (53). Sequencing of the sister’s RBP4 gene revealed two unique point mutations, resulting in amino acid changes to the RBP4 protein. Sequence analysis showed that these siblings inherited two mutated alleles (resulting in different amino acid substitutions on the encoded proteins) (53). As a result, both affected siblings experienced night blindness and modest retinal dystrophy, presumably due to insufficient retinoid delivery to the eye, but both showed no potentially severe symptoms of retinoid deficiency, such as an impaired immunity (53). Another family, living in South Asia and exhibiting a retinal degeneration, showed a similar total lack of RBP4. Two affected siblings experienced visual defects, but showed no signs of xerophthalmia (54). Exome sequencing showed abnormal changes in the RBP4 gene of these two affected patients but not in their unaffected sibling (54). These two siblings who completely lacked RBP4 protein had undetectable levels of serum retinol, whereas an unaffected sister had a more normal level of serum retinol (~1 µM). For both studies, TTR levels were reported to be normal, indicating that the patients had reduced RBP4 levels due to mutations in RBP4 itself, rather than due to lack of TTR (53,54). Studies in animal models agree with these findings from clinical studies—mice lacking RBP4 are also generally normal, aside from an impaired vision phenotype (55,56).
Hi @tim-2,
Thanks for sharing that.
I've read in other papers that LOW serum RBP levels are common in Schizophrenia, other psychiatric disorders, Autism, Alzheimer's, IBD, and especially so in cystic fibrosis. It’s odd that these authors don’t mention that. But, I think it is a big mistake to think that the low RBP (and vA) levels are somehow causal to the disease conditions. Rather, the question should be: what's actually happening to their dietary vA intake; where is it going to?
In one paper, it is stated that free retinol (not bound to the RBP) can pass through the cell’s outer membrane in about 1ms. So, if a person has a genetic condition that prevents the formation of the RBPs, or does not have adequate fat and protein in their diet, and they have even a reasonable amount of vA intake, then that vA is going to very quickly be moved from serum directly into the cells. From there it is going to be slowly converted into RA. It’s that RA that’s causing the disease conditions.
Moreover, it’s clear that the conversion of retinol to RA is not at all being “regulated” by the RBPs. Note the spike in RA after the consumption of liver. See table 1.
http://hbsn.amegroups.com/article/viewFile/3926/4896/20597
I found this statement interesting, and consistent with a lot of other recent studies.
Moreover, elevated levels of RBP (or RBP4), the sole specific blood transport protein for retinol, is proposed to be causally associated with the development of obesity-related metabolic disease, including impaired insulin responsiveness (and consequently type 2 diabetes), liver disease, and cardiovascular disease.
I think the answer to what’s causing metabolic disease, and diabetes, etc. is pretty much staring these researchers in the face, but they fail to see it because of the dogmatic and entrenched belief that vA is “essential.”
If you’ve not seen it, I discussed the topic of the RBPs in my blog post titled” The Retinol Binding Proteins as Antibodies”
https://ggenereux.blog/2019/08/05/the-retinol-binding-proteins-as-antibodies/
RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.
Based on the modern findings, I think it is rather obvious that the RBP can no longer be legitimately considered to be “transport and delivery” proteins. Primarily so because the RBPs are being synthesized in cells of many of the so-called target tissues. Clearly, these target cells are trying to get rid of the vA.
Also, I found it interesting that retinyl esters are being transported within LDLs, and for a long time now the LDL has been regarded as the “bad” form of cholesterol.
Thanks again,
Grant
Hi Grant,
The only symptoms RBP deficient people get are VAD eye symptoms which matches with the scientific consensus on VA's role in the body, that retinol is essential for the eye only. The symptoms they suffer from are not caused by RA toxicity which has a totally different symptom list. Because a tiny amount of retinol can be transported to the eye without RBP they don't go completely blind. This is strong evidence for retinol being essential for the eye.
The VA these people consume is being stored in the liver and then excreted via the bile just like the average person, they will only get VA toxicity if liver storage is overloaded just like the average person.
It's hard to know how much RA their tissues would be getting so it's hard to draw any conclusions there.
Elevated RBP is associated with Hypervitaminosis A which does seem to be the most obvious answer to the connection between high RBP's and metabolic disease. I would think RBP would elevate before retinol spilled into the blood so maybe it is a more useful marker of Hypervitaminosis A. I really hope that the answer to many of these diseases is as simple as cutting out high VA foods.
Yeah it is interesting that RBP can be synthesized outside of the liver. It could be synthesized outside the liver and then used by the liver or it could be made outside the liver in order to bind any retinyl esters in the blood.
Interesting observation about "bad" cholesterol and retinyl esters.
Cheers,
Tim
My impression is that in order for vitamin A to be excreted from the body it has to be transported out of the liver storage sites & into the blood (bound to RBP) & then back to the liver for metabolism via ADH, ALDH, CYP26 & glucoronidation (or alternative). I don’t think it generally goes straight from storage to the bile. Therefore these individuals with no RBP would accumulate retinyl esters in their liver I think as it would be stuck there unable to undergo the main metabolism route. This is my understanding. If I’m wrong very happy to learn.
Additional thoughts: according to Margaret Moss (very experienced UK nutritional therapist who has lots of interesting things to say) people who have had hepatitis are often lacking RBP & are more prone to vitamin A toxicity. Furthermore, people who can’t make enough RBP can show low serum retinol but this does not mean that they have low vA stores in liver - the opposite can be true. Having low RBP predisposes to vA toxicity I think.
https://www.gastrojournal.org/article/0016-5085(82)90133-0/pdf
I've been trying to find the answer to that but have come up dry. I would really appreciate if someone could link to a paper that answers this question.
People lacking RBP would quickly get sick with any VA in the diet if RBP was needed to eliminate VA. That isn't the case. They just get VAD eye symptoms.
I’ve been having a look for evidence of vA accumulation in liver with low RBP. There is this paper looking at alterations in vA during inflammation.
‘These results indicate that instead of being lost, retinol accumulated in the liver during inflammation and that hyporetinolemia was attributable to a decrease in the availability of hepatic RBP.’