Cholesterol Sulfate and the Sulfur Cycle

It seems to me that now is a good time to recapitulate what I have learned about cholesterol sulfate in my studies over the past several months, summarizing its roles, according to my understanding, and explaining the resulting pathology that arises when levels are depleted. I’m going to make this blog post as short and succinct as possible, in the hopes that people who may be getting lost in the details of the biology will be able to follow these high level arguments presented, I hope, in plain English.

Back when people spent a significant amount of their time outdoors, and hadn’t heard of sunscreen, they got plenty of sun exposure to the skin, and this allowed the eNOS in cells close to the surface layer of the skin to produce sulfate from sulfide and attach it to cholesterol. Some of the cholesterol sulfate got released into the blood stream, probably getting picked up by HDL-A1, and some of it ended up in the outer layer of the skin, where it plays a very important role in barrier function (keeping the skin water-tight and keeping out pathogenic bacteria). eNOS normally produces cholesterol sulfate not only in cells in the epidermis but also in cells that roam the blood, like platelets and RBCs. All of these cells contain functioning eNOS, and all of them produce cholesterol sulfate, which I do not think is a coincidence.

Today, due to our dietary avoidance of foods high in cholesterol and sulfur, and due to our sun avoidance and liberal use of sunscreen, we don’t get enough cholesterol sulfate supply, and this has huge ramifications everywhere. It’s most obvious, in my opinion, in the autism epidemic. In addition to their cognitive and social issues, autistic children have several characteristics that can be directly explained by cholesterol sulfate deficiency, namely, eczema, asthma, digestive problems, and increased susceptibility to infection.

I think preeclampsia (toxemia), a condition that now affects 6-8% of American pregnancies, and is rapidly increasing, is due to an insufficient supply of cholesterol sulfate for the fetus. To start with, cholesterol sulfate plays an essential role in fertilization. Furthermore, I believe that the fetus gets its entire supply of both cholesterol and sulfate from the cholesterol sulfate molecule, which can penetrate the placental barrier, unlike cholesterol. It has been shown that cholesterol sulfate shows up in profuse amounts in the placental villi in the last trimester of pregnancy, the same time during which preeclampsia develops. Preeclampsia is a very strong risk factor for future autism in the fetus.

In looking at heart disease, I think atherosclerosis develops as an alternative method to produce cholesterol sulfate, since the normal method through sunlight exposure to the skin has failed. As I’ve discussed before, the macrophages take up cholesterol from LDL and hand it over to HDL-A1, and the platelets combine the cholesterol from HDL-A1 with sulfate derived from homocysteine thiolactone (a process which requires superoxide and therefore ROS – reactive oxygen species) to produce cholesterol sulfate and release it to the blood.

What does the cholesterol sulfate do that’s so important? It supplies both cholesterol and sulfate to all the tissues. I cannot think of a more important thing to do! Sulfate plays an important role in the glycocalyx, which is a thick layer of attached glycosaminoglycans that decorate the artery wall, in keeping the blood and its suspended contents from seeping out into the tissues. Sulfate, a kosmotrope, pairs with sodium, a chaotrope, in the blood stream to maintain the appropriate kosmotrope/chaotrope balance that keeps proteins (and cells!) from salting-out/salting-in. What this means in plain English is that sulfate is needed to stabilize the blood. It’s clear from the research literature that cholesterol sulfate hangs out in the outer membrane of red blood cells, and it plays an important role in protecting them from falling apart.

I believe that RBC’s hand off cholesterol sulfate to the tissues (especially the heart, skeletal muscles, and neurons) as they pass through the capillaries. I further believe that muscles and neurons are able to process glucose in the caveolae of their cell membranes, using ferrous sulfate as a catalyst to help in the reaction converting glucose to pyruvate. Hydrogen peroxide is also required, and insulin will not induce GLUT4 to go to the membrane unless hydrogen peroxide is present. The reduction of the sulfur in sulfate to sulfide is a decoy exploiting the reducing power of glucose, to protect the cell’s proteins from glycation damage. The sulfur is first attached to pyruvate to form 3-mercaptopyruvate, and is then released from the pyruvate and easily passed into the blood stream as hydrogen sulfide, a signaling gas that has all the good properties of nitric oxide but none of the bad properties. The oxygen released from the sulfate anion is handed over to myoglobin in muscle cells or alpha-synuclein in neurons, and delivered to the mitochondria (safe oxygen transport).

When there isn’t enough cholesterol and sulfate to supply this process, the muscle cells become impaired in their ability to process glucose. This is the “insulin resistance” that is becoming a steadily increasing problem in modern society. Unlike the skeletal muscles, the heart muscle is protected from it, but only because the plaque is doing its job delivering a private stash of cholesterol sulfate to the heart.

The hydrogen sulfide that is produced by metabolizing glucose in the caveolae is eagerly taken up by the mitochodria of all the tissues (they prefer it over glucose as a source of energy!). The mitochondria convert hydrogen sulfide to thiosulfate, producing ATP in the process (this is well established). The thiosulfate is the source of sulfur that feeds into eNOS to produce two molecules of free sulfate from one molecule of thiosulfate (at least that’s my current model). This completes the sulfur cycle. Thus, hydrogen sulfide is oxidized to sulfate in the skin upon sun exposure (capturing the energy in sunlight), and then the sulfate is reduced back to sulfide in the caveolae of muscles (and probably also neurons), using glucose as the reducing agent.

When an individual becomes so deficient in cholesterol and sulfur and sunlight exposure that they can no longer maintain the sulfur cycle, their body converts to a nitrogen-based oxygen transport mechanism. This has the advantage that it doesn’t depend on cholesterol, but the disadvantage that nitrate does not hang out in the extracellular matrix proteins the way sulfate does. So I think it has to be continually produced and excreted through the urine. Eventually, sources of nitrogen become depleted, and the person ends up with cachexia, a muscle-wasting disease.

When you switch to nitrogen-based oxygen transport, you also have to adjust the cations to reflect the fact that nitrate is a chaotrope instead of a kosmotrope. This is why calcium entry into a cell causes eNOS to switch from producing sulfate to producing nitrate. Calcium is a kosmotrope, whereas potassium is a chaotrope. So you have the following possible pairs in the cell:


potassium-sulfate: chaotrope-kosmotrope
calcium-nitrate: kosmotrope-chaotrope


I think the system is rather elegant, because, when the cell becomes depleted in cholesterol, it starts leaking small ions through its membrane, such as potassium and sodium. It will exhaust itself, consuming all of its ATP, in trying to keep these ions on the right side of the fence. So, instead, it converts to calcium-nitrate instead of potassium-sulfate, because calcium is a much bigger ion and won’t leak. It has to switch the anions in order to balance the kosmotrope/chaotrope situation.

So, another thing that happens when you switch from sulfur-based to nitrogen-based oxygen transport is that calcium gets leached from the bones, so that it can buffer the nitrates in the blood and in the cells. Arteries become calcified (”hardened”) and heart valves become calcified, while the person simultaneously develops osteoporosis.

People’s bodies react differently to these deficiencies depending on their genotype. Many people develop a condition that reflects an attempt to raid sulfate from one or more sites in the body, in order to be able to stay with sulfur-based oxygen transport rather than switching to nitrogen-based oxygen transport. Some people develop arthritis, which raids sulfate from the ligaments surrounding joints. Other people develop digestive problems like

Crohn’s disease and colitis, which raids sulfate from the stomach lining. Other people get multiple sclerosis, raiding sulfate from the myelin sheath in axons in neurons. Other people end up with destroyed beta cells in the pancreas (type 1 diabetes) due to a depletion of heparan sulfate in the pancreas.

To summarize, I believe that cholesterol sulfate deficiency is behind many if not all of the chronic diseases facing us today. The solution to the problem is incredibly simple: eat more foods that are rich in cholesterol and sulfur, and get more sun exposure to the skin.