The metabolic syndrome is a term used to encapsulate a complex set of markers associated with increased risk to heart disease. The profile includes (1) insulin resistance and dysfunctional glucose metabolism in muscle cells, (2) excess triglycerides in the blood serum, (3) high levels of LDL, particularly small dense LDL, the worst kind, (4) low levels of HDL (the “good” cholesterol) and reduced cholesterol content within the individual HDL particles, (5) elevated blood pressure, and (6) obesity, particularly excess abdominal fat. I have argued previously that this syndrome is brought on by a diet that is high in empty carbohydrates (particularly fructose) and low in fats and cholesterol, along with a poor vitamin D status [Seneff2010]. While I still believe that all of these factors are contributory, I would now add another factor as well: insufficient dietary sulfate.
I have described in a previous essay, my interpretation of obesity as being driven by a need for abundant fat cells to convert glucose to fat because the muscle cells are unable to efficiently utilize glucose as fuel. With sulfur deficiency comes the answer as to why muscle cells would be defective in glucose management: they can’t come up with enough cholesterol sulfate to seed the lipid raft needed to import the glucose.
An alternative way to ovecome a muscle cell’s defective glucose metabolism is to exercise vigorously, so that the generated AMPK (an indicator of energy shortage) induces the GLUT4 to migrate to the membrane even in the absence of insulin [Ojuka2002]. Once the glucose is inside the muscle cell, however, the iron-sulfate mechanism just described is dysfunctional, both because there’s no cholesterol sulfate and because there’s no hydrogen peroxide. Additionally, with intensive exercise there’s also a reduced supply of oxygen, so the glucose must be processed anaerobically in the cytoplasm to produce lactate. The lactate is released into the blood stream and shipped to the heart and brain, both of which are able to use it as fuel. But the cell membrane remains depleted in cholesterol, and this makes it vulnerable to future oxidative damage.
Another way to compensate for defective glucose metabolism in the muscle cells is to gain weight. Fat cells must now convert glucose into fat and release it into the blood stream as triglycerides, to fuel the muscle cells. In the context of a low fat diet, sulfur deficiency becomes that much worse a problem. Sulfur deficiency interferes with glucose metabolism, so it’s a much healthier choice to simply avoid glucose sources (carbohydrates) in the diet; i.e. to adopt a very low-carb diet. Then the fat in the diet can supply the muscles with fuel, and the fat cells are not burdened with having to store up so much reserve fat.
Insulin suppresses the release of fats from fat cells [Scappola1995]. This forces the fat cells to flood the bloodstream with triglycerides when insulin levels are low, i.e., after prolonged periods of fasting, such as overnight. The fat cells must dump enough triglycerides into the bloodstream during fasting periods to fuel the muscles when the dietary supply of carbohydrates keeps insulin levels elevated, and the release of fats from the fat cells is repressed. As the dietary carbs come in, blood sugar levels rise dramatically because the muscle cells can’t utilize it.
The liver also processes excess glucose into fat, and packages it up into LDL, to further supply fuel to the defective muscle cells. Because the liver is so preoccupied with processing glucose and fructose into LDL, it falls behind on the generation of HDL, the “good” cholesterol. So the result is elevated levels of LDL, triglycerides, and blood sugar, and reduced levels of HDL, four key components of the metabolic syndrome.
The chronic presence of excess glucose and fructose in the blood stream leads to a host of problems, all related to glycation damage of blood stream proteins by glucose exposure. One of the key proteins that gets damaged is the apolipoprotein, apoB, that’s encased in the membrane of the LDL particles. Damaged apoB inhibits the ability of LDL to efficiently deliver its contents (fat and cholesterol) to the tissues. Fat cells again come to the rescue, by scavenging the broken LDL particles (through a mechanism that does not require apoB to be healthy), taking them apart, and extracting and refurbishing their cholesterol. In order to function properly, the fat cells must have intact ApoE, an antioxidant that cleans up oxidized cholesterol and transports it to the cell membrane for delivery to HDL particles.
Fat Cells, Macrophages and Atherosclerosis
While diligently converting glucose to stored fats, the fat cells are awash in glucose, which damages their apoE through glycation [Li1997]. Once their apoE is damaged, they can no longer transport cholesterol to the membrane. Excess cholesterol accumulates inside the fat cells and eventually destroys their ability to synthesize proteins. Concurrently, their cell membrane becomes depleted in cholesterol, because they can no longer deliver it to the membrane [Seneff2010]. A fat cell that has deteriorated to this degree has no choice but to die: it sends out distress signals that call in macrophages. The macrophages essentially consume the dysfunctional fat cell, wrapping their own membrane around the fat cell’s membrane that is now barely able to hold its contents inside [Cinti2005].
Macrophages are also principle players in the fatty streaks that appear along the sides of major arteries leading to the heart, and are associated with plaque build-up and heart disease. In a fascinating set of experiments, Ma et al. [Ma2008] have shown that the sulfate ion attached to oxidized forms of cholesterol is highly protective against fatty streaks and atherosclerosis. In a set of in-vitro experiments, they demonstrated diametrically opposite reactions from macrophages to 25-hydroxyl cholesterol (25-HC) versus its sulfoconjugate 25-hydroxyl cholesterol sulfate (25-HC3S). Whereas 25-HC present in the medium causes the macrophages to synthesize and store cholesterol and fatty acids, 25-HC3S has the exact opposite effect: it promotes the release of cholesterol to the medium and causes fat stores to shrink. Furthermore, while 25-HC added to the medium led to apoptosis and cell death, 25-HC3S did not. I suggest that the sulfate radical is essential for the process that feeds cholesterol and oxygen to the heart muscle.
Sulfur and Alzheimer’s
With an aging population, Alzheimer’s disease is on the rise, and it has been argued that the rate of increase is disproportionately high compared to the increase in the raw number of elderly people [Waldman2009]. Because of a conviction that the amyloid beta plaque that is a signature of Alzheimer’s is also the cause, the pharmaceutical industry has spent hundreds of millions, if not billions, of dollars pursuing drugs that reduce the amount of plaque accumulating in the brain. Thus far, drug trials have been so disappointing that many are beginning to believe that amyloid beta is not the cause after all. Recent drug trials have shown not only no improvement, but actually a further decline in cognitive function, compared to placebo ( New York Times Article). I have argued elsewhere that amyloid beta may actually be protective against Alzheimer’s, and that problems with glucose metabolism are the true culprit in the disease.
Once I began to suspect sulfur deficiency as a major factor in Americans’ health, I looked into the relationship between sulfur deficiency and Alzheimer’s. Imagine my surprise when I came upon a web page posted by Ronald Roth, which shows a plot of the levels of various minerals in the cells of a typical Alzheimer’s patient relative to the normal level. Remarkably, sulfur is almost non-existent in the Alzheimer’s patient’s profile.
To quote directly from that site: “While some drugs or antibiotics may slow, or if it should happen, halt the progression of Alzheimer’s disease, sulfur supplementation has the potential of not only preventing, but actually reversing the condition, provided it has not progressed to a stage where much damage has been done to the brain.”
“One major reason for the increase in Alzheimer’s disease over the past years has been the bad reputation eggs have been getting in respect to being a high source of cholesterol, despite the fact of dietary intake of cholesterol having little impact on serum cholesterol – which is now also finally acknowledged by mainstream medicine. In the meantime, a large percentage of the population lost out on an excellent source of sulfur and a host of other essential nutrients by following the nutritional misinformation spread on eggs. Of course, onions and garlic are another rich source of sulfur, but volume-wise, they cannot duplicate the amounts obtained from regularly consuming eggs.”
Why should sulfur deficiency be so important for the brain? I suspect that the answer lies in the mysterious molecule alpha-synuclein, which shows up alongside amyloid-beta in the plaque, and is also present in the Lewy Bodies that are a signature of Parkinson’s disease [Olivares2009]. The alpha-synuclein molecule contains four methionine residues, and all four of the sulfur molecules in the methionine residues are converted to sulfoxides in the presence of oxidizing agents such as hydrogen peroxide [Glaser2005]. Just as in the muscle cells, insulin would cause the mitochondria of neurons to release hydrogen peroxide, which would then allow the alpha-synuclein to take up oxygen, in a way that is very reminiscent of what myoglobin can do in muscle cells. The lack of sufficient sulfur should directly impact the neuron’s ability to safely carry oxygen, again paralleling the situation in muscle cells. This would mean that other proteins and fats in the neuron would suffer from oxidative damage, leading ultimately to the neuron’s destruction.
In my essay on Alzheimer’s, I argued that biologically pro-active restriction in glucose metabolism in the brain (a so-called type-III diabetes and a precursor to Alzheimer’s disease) is triggered by a deficiency in cholesterol in the neuron cell membrane. Again, as in muscle cells, glucose entry depends upon cholesterol-rich lipid rafts, and, when the cell is deficient in cholesterol, the brain goes into a mode of metabolism that prefers other nutrients besides glucose.
I suspect that a deficiency in cholesterol would come about if there is insufficient cholesterol sulfate, because cholesterol sulfate likely plays an important role in seeding lipid rafts, while concurrently enriching the cell wall in cholesterol. The cell also develops an insensitivity to insulin, and, as a consequence, anaerobic metabolism becomes favored over aerobic metabolism, reducing the chances for alpha-synuclein to become oxidized. Oxidation actually protects alpha-synuclein from fibrillation, a necessary structural change for the accumulation of Lewy bodies in Parkinson’s disease (and likely also Alzheimer’s plaque) [Glaser2005]