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Expression of Vitamin A-related genes increases with BMI
Quote from Jenny on October 11, 2021, 8:07 amI don’t know. It’s all theory. The data that Johannes produced seems to say that less ISX is expressed at higher BMI (unless I’ve interpreted wrongly). ISX suppresses the proteins that absorb and convert betacarotene to retinal. Lack of ISX would suggest that this negative feedback is working less well. Less suppression is taking place which means more absorption and conversion. I would suspect it’s to do with liver health as well as BMI, but that’s just a guess. I think that vA toxicity messes up this helpful negative feedback loop that prevents too much betacarotene being absorbed. So yes I’d say the sicker the person (BMI and/or liver health) the more harm caused by betacarotene foods. This is all theory and largely from anecdotal observations, but correlates with my experiences. Clearly the idea that people can’t become toxic from carotenoid intake, due to the negative feedback loop, is incorrect.
Edit: Another interesting paper. https://pubmed.ncbi.nlm.nih.gov/20061533/
Interesting information
I am currently at a BMI of 22.8. My flares of my illnesses are usually triggered when I get up to a BMI of 28 for a decent amount of time.
I was wondering if these BMI events take muscle mass into account. I know when I was weight training I was at a 28 but I sure as hell wasn't lean. I was pudgey as shit. I would guess about 30 pounds of fat. If I had been lean at a BMI of 28 via muscle mass increase only, would the events outlined above have happened? Or does it require ones to have a decent about of lard?
Wow Johannes. I need to go through your post slowly! Thanks for the summary. That makes a whole lot of sense. There must be a tipping point where as the protective mechanisms stop working, everything gets a whole lot worse. More toxin is absorbed and converted and cell membrane damage is not repaired. Cell membranes are key to health.
Unfortunately I only just now found out that retinol can also be hydroxylated at the 4 position (for example by the Vitamin D-related CYP27C1), forming (4S)/(4R)-hydroxyretinol and 4-oxo-retinol, so right now I am more uncertain than ever before about what actually happens to retinol in the liver. About 10–15% of total retinol was converted to 4-oxo-retinol in embryonic F9 teratocarcinoma cells (Achkar, Derguini et al. 1996). Importantly, 4-oxo-retinol, but not retinol, activates RAR receptors and was found to inhibit proliferation of epithelial cells almost as much as all-trans-retinoic acid (Liu, Derguini et al. 2009). Additionally, differentiated “less aggressive” NB4 cancer cells were found to synthesize 10x more 4-oxo-retinol that undifferentiated NB4 cells after treatment with all-trans-retinol (Faria, Rivi et al. 1998), and it can apparently be esterified to 4-oxo-retinyl palmitate.
It completely blows my mind how this apparently highly potent retinol metabolite hasn’t really been investigated since it was discovered in the nineties, kind of like how the endogenous RXR ligand (which is likely 9-cis-13,14-dihydroretinoic acid, NOT 9-cis-retinoic acid) was not discovered until 2015. Seriously, how can anyone claim that retinol is a vitamin when we don’t even know what its in vivo metabolites are, which of the 50+ enzymes showing activity towards retinol actually metabolizes it, and which enzyme hydrolyzes the retinyl esters? It feels like every time I figure something out I'm back at square one the next day.
Quote from Armin on October 12, 2021, 11:36 amI was wondering if these BMI events take muscle mass into account. I know when I was weight training I was at a 28 but I sure as hell wasn't lean. I was pudgey as shit. I would guess about 30 pounds of fat. If I had been lean at a BMI of 28 via muscle mass increase only, would the events outlined above have happened? Or does it require ones to have a decent about of lard?
Since the data I’ve been analyzing was from studies investigating obesity or NAFLD I think it’s fair to assume that higher BMIs are a result of increased body fat and not increased muscle mass, at least for the liver samples.
Quote from Jenny on October 13, 2021, 2:35 amWow Johannes. I need to go through your post slowly! Thanks for the summary. That makes a whole lot of sense. There must be a tipping point where as the protective mechanisms stop working, everything gets a whole lot worse. More toxin is absorbed and converted and cell membrane damage is not repaired. Cell membranes are key to health.
I would assume that the tipping point is around BMI 22.5–25 when hepatic stellate cells stop expressing STRA6 and the retinol is released into the bloodstream. Biomarkers for the activation of HSCs (i.e. oxidation of retinol) first appear in adipose tissue in the BMI 22.5–25 range and seem to peak around BMI 27.5–30 (image below), but strangely the reverse was true for the human liver samples. I’m starting to think that the adipose tissue samples might be a better model for HSCs than the liver samples, since HSCs seem to have the same biological function as adipocytes, however HSCs express LRAT which adipocytes apparently do not.
Bibliography
Achkar, C. C., F. Derguini, B. Blumberg, A. Langston, A. A. Levin, J. Speck, R. M. Evans, J. Bolado, K. Nakanishi, J. Buck and L. J. Gudas (1996). "4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors." Proceedings of the National Academy of Sciences of the United States of America 93(10): 4879-4884.
Faria, T. N., R. Rivi, F. Derguini, P. P. Pandolfi and L. J. Gudas (1998). "4-Oxoretinol, a metabolite of retinol in the human promyelocytic leukemia cell line NB4, induces cell growth arrest and granulocytic differentiation." Cancer research 58(9): 2007-2013.
Liu, L., F. Derguini and L. J. Gudas (2009). "Metabolism and regulation of gene expression by 4-oxoretinol versus all-trans retinoic acid in normal human mammary epithelial cells." Journal of cellular physiology 220(3): 771-779.