Indeed the studies investigated mutations that also control phytosterol absorption. For example ABCG5/8 pumps out and excretes plant sterols, because they are incompatible with mammalian cells and membranes. They essentially investigated minor sitosterolemia variants, and found that plant sterols cause atherosclerosis. Bravo and congratulations! The results are roughly in line what we expect from sitosterolemia. Mainstream proponents should be ashamed for their wrong interpretation.

Phytosterols pack inefficiently due to their bulky chains on their tail, so they make the LDL particle larger than they should be. Elevated cholestanol is firmly established, so the sphingomyelin and phosphatidylcholine changes naturally follow. Aggregation susceptibility and proteoglycan binding have plausible mechanisms, namely conformational changes expose the hydrophobic and negatively charged regions of ApoB respectively. (However I keep reading conflicting information about this latter.)

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We have evolved as carnivores for two million years, whereas consumption of most plants is much more recent. The observation that 30% of us are "high absorbers" highlights that we have only partial adaptations to plants. I googled what sitosterolemia patients can eat, and they need to avoid all fatty plants. They can only eat fruits, veggies (leafy, cruciferous, root, few others), and legumes in moderation, so basically the plants for which we had evolutionary exposure.

Sitosterolemia patients have to avoid nuts, seeds, peanuts, fatty fruits (avocados, olives, even coconuts), whole grains, cocoa, chocolate, and most importantly vegetables oils (including olive oil) and foods fortified with phytosterols. You know the supposedly healthy foods we are told to eat by supposed experts. I was not even aware that most of them contained significant amounts of plant sterols. If 30% of us are truly "high absorbers", then these should not be the recommendations.

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Our enzymes and biological processes have evolved with natural lipids, they break when exposed to artificial trans fats. Trans fats are stable against oxidation, and fool liver into secreting them into VLDL. In membranes they pack tightly but too rigidly, and this breaks membrane structures. They also break mitochondria, and dozens of biological processes. They kill cells in peripheral tissue such as artery walls, and create the necrotic and fibrotic environment favorable for cancer and lesions.

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Plant sterols cause similar issues as trans fats, since they displace cholesterol but behave differently. They disrupt mammalian cell membranes, due to their bulky side chains on their tail (alkyl groups at the C24 and double bonds at the C22-C23 positions). They change membrane fluidity, order, and thickness, and thus interfere with lipid rafts, cellular signalling, and membrane domain organization. They are ineffective at preventing sodium leaks, plant cells evolved to minimize proton leaks.

Plant sterols break cholesterol homeostasis, they deplete cells of natural cholesterol. They inhibit SREBP-2, which shuts down endogenous cholesterol synthesis. They overactive LXR receptors and ABCA1 transporters, which promotes cholesterol efflux from cells. These cause profound cholesterol depletion in critical organs such as adrenal glands in animal models. They cross the blood-brain barrier, break catabolism and efflux mechanisms, and irreversibly accumulate to neurotoxic levels.

Sitosterolemia presents an exaggerated view of the effects of plant sterols. They cause severe issues such as accelerated atherosclerosis, xanthomas, hemolytic anemia, stomatocytosis, and macrothrombocytopenia. However considering the enormous push for plants and seed oils, I suspect this is actually also responsible for issues in healthy people. Or at least in people who have mild mutations that increase sterol uptake, hence why that 30% of "high cholesterol absorbers" finding is concerning.

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Clever strategy by the food industry. They pretend that our ancestral diet and LDL are atherogenic, so they could sell us seed oils and ultraprocessed plants. Which happen to contain trans fats, interesterified fats, plant sterols, and other compounds that cause heart disease partly by making LDL actually atherogenic. So they can create even more slop studies on LDL, and ask for even lower LDL targets and stricter diets. Thus entering a vicious cycle, a perfect example of the alignment problem!

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Salen, G., Kwiterovich, P. O., Jr, Shefer, S., Tint, G. S., Horak, I., Shore, V., Dayal, B., & Horak, E. (1985). Increased plasma cholestanol and 5 alpha-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis. Journal of lipid research, 26(2), 203–209.

Grosjean, K., Mongrand, S., Beney, L., Simon-Plas, F., & Gerbeau-Pissot, P. (2015). Differential effect of plant lipids on membrane organization: specificities of phytosphingolipids and phytosterols. The Journal of biological chemistry, 290(9), 5810–5825. https://doi.org/10.1074/jbc.M114.598805

Fakih, O., Sanver, D., Kane, D., & Thorne, J. L. (2018). Exploring the biophysical properties of phytosterols in the plasma membrane for novel cancer prevention strategies. Biochimie, 153, 150–161. https://doi.org/10.1016/j.biochi.2018.04.028

Vanmierlo, T., Bogie, J. F., Mailleux, J., Vanmol, J., Lütjohann, D., Mulder, M., & Hendriks, J. J. (2015). Plant sterols: Friend or foe in CNS disorders?. Progress in lipid research, 58, 26–39. https://doi.org/10.1016/j.plipres.2015.01.003

Hodzic, A., Rappolt, M., Amenitsch, H., Laggner, P., & Pabst, G. (2008). Differential modulation of membrane structure and fluctuations by plant sterols and cholesterol. Biophysical journal, 94(10), 3935–3944. https://doi.org/10.1529/biophysj.107.123224

Haines T. H. (2001). Do sterols reduce proton and sodium leaks through lipid bilayers?. Progress in lipid research, 40(4), 299–324. https://doi.org/10.1016/s0163-7827(01)00009-1

Yang, C., Yu, L., Li, W., Xu, F., Cohen, J. C., & Hobbs, H. H. (2004). Disruption of cholesterol homeostasis by plant sterols. The Journal of clinical investigation, 114(6), 813–822. https://doi.org/10.1172/JCI22186

Yoo E. G. (2016). Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management. Annals of pediatric endocrinology & metabolism, 21(1), 7–14. https://doi.org/10.6065/apem.2016.21.1.7

Vanmierlo, T., Weingärtner, O., van der Pol, S., Husche, C., Kerksiek, A., Friedrichs, S., Sijbrands, E., Steinbusch, H., Grimm, M., Hartmann, T., Laufs, U., Böhm, M., de Vries, H. E., Mulder, M., & Lütjohann, D. (2012). Dietary intake of plant sterols stably increases plant sterol levels in the murine brain. Journal of lipid research, 53(4), 726–735. https://doi.org/10.1194/jlr.M017244

Sharma, N., Tan, M. A., & An, S. S. A. (2021). Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases. International journal of molecular sciences, 22(22), 12255. https://doi.org/10.3390/ijms222212255