Is increased cholesterol production a rescue mechanism for electron export?

A provocative study was recently published showing that elevated cholesterol is better managed by twelve Oreo cookies a day than by traditional statin treatment. Of course, only in a special situation, but that's how it is. That situation is a very low-carbohydrate diet combined with low body fat. This led me to think that increased cholesterol is probably a way to solve some metabolic problem, specifically a lack of intermediate products of the TCA cycle. These are necessary for the export of energetic electrons through membranes, i.e. for the transfer of beta oxidation products (NADH) from peroxisomes to the cytosol and further to the mitochondria. In the case of a low-carbohydrate keto diet, electrons obtained by beta oxidation of fats in perixosomes can't be exported via the normal pathway via lactate or malate, but cholesterol synthesis as rescue mechanism can be used. And I even found a study that pretty much confirms it.

Cholesterol synthesis is a relatively complex matter that takes place partly in peroxisomes. These are the cellular shredders of unusual fats. The common ones are processed in the mitochondria, but very long, branched or polyunsaturated fats, for example, are chopped into smaller pieces right here. At the same time, among other things, NADH molecules are created, an intermediate fuel for processing in the mitochondria, containing energetic electrons for obtaining energy by oxidation to water. And this is where the problem arises, because they have to get out but these molecules do not pass through the membranes. What to do with this? Cyclic transport shuttle mechanisms using intermediate products of the TCA cycle, pyruvate, lactate, malate, citrate or oxaloacetate, mostly products of glucose metabolism, are used. However, these substances are deficient in the ketogenic diet, that is the principle of ketosis.

Cholesterol synthesis appears to be an efficient method for transferring NAD(P)H from the peroxisome and mitochondria under this situation. In obese people, the formation of glucose by gluconeogenesis from glycerol or amino acids is usually quite active. So there is no such shortage. But in some lean people, gluconeogenesis seems to be insufficient, there will be a lack of transport intermediates, and cholesterol synthesis will become the solution for electron export from peroxisomes. So this may be where the unusually high LDL-C cholesterol levels in some perfectly healthy people come from. Supplementing with a small amount of carbohydrates will solve this problem.

The effect of lovastatin, suppressing of cholesterol synthesis increases NAD(P)H levels, causes NAD(P)+ deficiency, and increases ROS generation by activating NADPH oxidase (NOX), which damages cells by excessive H2O2 generation.

Synthesis of cholesterol and downstream products converts NADPH to NADP+, similar to part of the transmembrane transport shuttle.

Transport of NAD(P)H by isocitrate dehydrogenase (IDH2/IDH1) from the mitochondrion to the cytosol. Transport from peroxisomes under normal conditions is similar but not as well studied. In the case of a keto diet, this transport is slowed or stopped due to a lack of oxaloacetate for the transport cycle to function properly. This process may also explain the decrease in cholesterol synthesis caused by omega-6 linoleic acid, as it also converts NADPH to NADP+ by involving the enzyme 2,4 dienoyl-CoA reductase (DECR) and reduces the need for cholesterol production for electron transport purposes.

Today, cholesterol is seen as the main cause of cardiovascular problems. But many doctors and scientists consider it a big mistake. Statistics show us that even genetically determined familial hypercholesterolemia does not have to be a big problem. A slightly increased mortality occurs up to the age of 40, but for older age groups the death rate is lower than average. This information comes from the scientific papers highlighted by David Diamond, PhD in his video. It also contains a lot of other information, although the main problem is increased blood clotting and an increased proportion of sdLDL (small dense LDL), i.e. small oxidized LDL particles. This agrees very well with the fact that increasing cholesterol production by activating PPARα with fenofibrate improves survival in the case of NADH oxidation problems at the first mitochondrial complex in the mitochondria.

Fenofibrate activates cholesterol production.

Activation of fat metabolism in peroxisomes by fenofibrate reduces oxidative stress and prolongs life.

Genetic familial hypercholesterolemia in the middle aged and older people reduces the risk of death.

Increased blood clotting (Prothrombin) increases the risk of cardiovascular diseases.

Fibrinogen, as an indicator of blood clotting tendency, represents a risk of higher incidence of cardiovascular diseases at any age.

Small oxidized sdLDL particles predict heart attack risk.

And I'll come back to the cholesterol-lowering results of cookies on the ketogenic diet. It could be deduced from the results that the effort to maximally exclude carbohydrates from the diet may not be good. Perhaps a better strategy is with a relatively small amount of carbohydrates (e.g. up to 130 g) and supplementing with ketones or perhaps MCT oil, from which the body can safely produce ketones without the need to use cholesterol production as a method to reduce oxidative stress.