Fat and Cholesterol:  misunderstood molecules

Starting in the 1970s and until recently, fat and cholesterol were vilified as the cause of coronary artery disease (CAD).  Those of us born in the 1980s and earlier will probably remember the 'food pyramids' with grains at their base, and oils and fats at the top -- with instructions to use these sparingly -- promoted widely by public health agencies.  And the low-fat food craze that took over in the 1980s and 90s -- guess what replaced the fat in those foods?  That's right, sugar.

Research has shown, however, that dietary fat and cholesterol are not the cause of coronary artery disease:

"Coronary artery disease pathogenesis and treatment urgently requires a paradigm shift. Despite popular belief among doctors and the public, the conceptual model of dietary saturated fat clogging a pipe is just plain wrong. A landmark systematic review and meta-analysis of observational studies showed no association between saturated fat consumption and (1) all-cause mortality, (2) coronary heart disease (CHD), (3) CHD mortality, (4) ischaemic stroke or (5) type 2 diabetes in healthy adults.1 Similarly in the secondary prevention of CHD there is no benefit from reduced fat, including saturated fat, on myocardial infarction, cardiovascular or all-cause mortality.2 It is instructive to note that in an angiographic study of postmenopausal women with CHD, greater intake of saturated fat was associated with less progression of atherosclerosis whereas carbohydrate and polyunsaturated fat intake were associated with greater progression [emphasis added].3"

On the contrary, excess consumption of refined carbohydrates (starches and sugar), leading to insulin resistance, is the root cause of CAD and other chronic diseases -- not dietary cholesterol, saturated fats, or meat.

Insulin Resistance

Insulin is a hormone released by the beta cells of the pancreas whose job, when bound to cells' insulin receptors, is to allow glucose (blood sugar) to enter from the blood stream into our body's cells.  Glucose is the fuel that the cells use to make energy and perform their functions.  We can get glucose by eating carbohydrates -- starches and sugar -- but the liver can make glucose from protein and fat, if a person consumes few or no carbohydrates.

    "Insulin resistance means that your body has become less sensitive to the effects of insulin, a powerful hormone released after meals that tells your body what to do with the calories you eat.... If you eat too much sugar and/or starch too often, as most people do, your blood glucose will spike frequently and your body will have to release lots of insulin over and over again to deal with those glucose spikes. Eventually your cells can become so accustomed to insulin spikes that they become less responsive to insulin. If your cells become numbed to insulin's signals, they can't absorb extra glucose from the bloodstream as well, and your blood sugar could stay too high for too long after meals. In response, the body releases even more insulin to try to get cells to respond better. One result of this vicious cycle can be type 2 diabetes, a disease marked by high blood sugar and high insulin levels."

    How and why does insulin resistance, the cells' "becoming numbed to insulin's signals," develop?  This is where the liver comes in, because it plays a central role in metabolizing glucose and regulating the body's response to insulin release by the pancreas. 

    The liver's central role in glucose metabolism and orchestrating the effects of insulin

    As mentioned above, one of insulin's functions is to enable cells to transport glucose inside the cell, where it can be used by the cell to make energy.  Most cells have insulin receptors, most notably the liver, muscle, fat, brain and pancreatic beta cells.

    But more than regulating glucose metabolism and homeostasis, insulin regulates growth.  It does this by directing what the liver does in the presence of glucose under varying circumstances.  After a meal containing carbohydrates (starches or sugar), the digestive system quickly breaks down the carbohydrates into glucose and releases it into the blood stream.  The liver is the first organ that encounters this spike in blood sugar:

    "Under the influence of insulin, your liver can do any of following things with the new glucose load [after a meal], depending on your body’s needs at the time:

    Burn it or ferment it for energy (ATP). If liver [and the body's other] cells need energy to conduct their cellular business, glucose will be chopped in half in preparation for burning in the mitochondria (your cellular furnace)....

    Transform it into 5-carbon building blocks (ribulose-5-phosphate) plus powerful helper molecules (NADPH) required to build components of new or growing cells, such as proteins, RNA, and DNA....

    Store it as glycogen or fat. In a process called glycogenesis, the liver strings glucose molecules into long chains of animal starch called glycogen, which is stored in the liver. If the liver’s glycogen tank is already full, glucose can be turned into fat instead (lipogenesis). The healthy liver doesn’t store much fat; it prefers to ship it out to other cells by releasing it into the bloodstream as triglycerides."

    And here we can see where problems might begin.  What happens if you consume excess amounts of carbohydrates -- in particular refined carbohydrates like white flour and sugar -- and too often, as most modern humans living in the US do?

    What happens is that the liver begins to churn out a lot of triglycerides and circulate them for storage in the body's fat cells.  This happens because you are consuming more carbohydrates than are needed to be burned for energy.  This increased circulation of triglycerides and the build-up of excess fat is how eating excess carbohydrates makes you overweight and obese, and underlies the mechanism of insulin resistance.

    The mechanism of insulin resistance:  excess circulating triglycerides interfere with intracellular insulin signaling

    These excess triglycerides and their free fatty-acid by-products circulating in the blood work their way into cells.  There they begin to disrupt the cell's insulin signaling pathway.

    Normally, after a spike in blood sugar, insulin arrives on a cell's insulin receptor and signals the cell to open its glucose transport channel (GLUT) to allow glucose inside the cell to be burned for energy.

    But with the cell's insulin signaling pathway interfered with by triglycerides and free fatty acids, the glucose transport channel remains closed and glucose cannot get inside the cell, but instead remains in the blood stream.

    The beta cells of the pancreas detect the still-elevated blood glucose levels and release yet more insulin into the blood stream.  And thus the vicious cycle of insulin resistance begins.

    This lecture by medical educator Dr. Mobeen Syed beautifully explains the mechanism underlying insulin resistance:

    The result of insulin resistance:  hyperglycemia, hypertriglyceridemia, glycated proteins, oxidation, and chronic inflammation

    Over time, as insulin resistance becomes progressively worse, and blood sugar levels remain chronically elevated, a variety of damage occurs in the body by the following mechanisms:

    Glycation:  "excess blood sugar can bind to vital proteins, DNA, RNA, and fats in the body and damage them, sometimes beyond repair. This process is called “glycation”. Think of it this way: sugars make proteins sticky. Proteins are supposed to be able to fold and move in special ways to perform their various special functions, but they can’t do that if sugar is gumming up the works. When sugars bind permanently to proteins, they turn the proteins into nuisance compounds called “Advanced Glycation End Products” or AGE’s. AGE’s have been linked to a wide variety of chronic diseases, including heart disease, kidney failure, diabetic retinopathy, Alzheimer’s disease, and aging."

    Oxidation:  "Fast carbs [refined carbohydrates] are “pro-oxidants.” This means that they have the power to damage important body molecules, such as DNA, by stealing their electrons away from them. Pro-oxidants are the opposite of anti-oxidants; they fight against each other.... Oxidative damage caused by pro-oxidants such as sugars can be the first step towards serious problems, such as cancer (by damaging DNA) and heart disease (by oxidizing cholesterol)."

    Inflammation:  "Both glycation and oxidation trigger inflammation in the body. Physicians and scientists have come to understand that most common chronic diseases are rooted in inflammation. This is not necessarily the kind of inflammation we can see or feel—it is usually on a much smaller scale that we may not be aware of. For example, the cholesterol plaques that block arteries to the heart and cause heart attacks are found to contain all the mini-markers of inflammation when you look at them under a microscope. Even diseases such as depression are associated with mini-markers of inflammation."

    This lecture by Dr. Mobeen Syed reviews with wonderful clarity the damage that can accrue in various bodily systems as a result of the glycation, oxidation and inflammation that occur due to the chronically elevated blood sugar caused by insulin resistance:

    The carbohydrate hypothesis of coronary artery disease and other chronic diseases

    Thus it seems like a good idea to limit the consumption of carbohydrates -- in particular refined carbohydrates, which cause the fastest, largest spikes in blood sugar -- in order to keep our blood sugar levels steady, and to avoid inducing insulin resistance.

    Indeed, there is growing scientific and medical consensus in the past decade or so that the diseases of modern, Western civilization are caused by the over-consumption of refined carbohydrates in the modern, Western diet.  These diseases include cardiovascular disease, which is the leading cause of death in the United States:

    "Decades of emphasis on the primacy of lowering plasma cholesterol, as if this was an end in itself and driving a market of ‘proven to lower cholesterol’ and ‘low-fat’ foods and medications, has been misguided. Selective reporting may partly explain this misconception. Reanalysis of unpublished data from the Sydney Diet Heart Study and the Minnesota coronary experiment reveal replacing saturated fat with linoleic acid containing vegetable oils increased mortality risk despite significant reductions in LDL and total cholesterol (TC) [emphasis added].7

    A high TC to high-density lipoprotein (HDL) ratio is the best predictor of cardiovascular risk (hence this calculation, not LDL, is used in recognised cardiovascular risk calculators such as that from Framingham). A high TC to HDL ratio is also a surrogate marker for insulin resistance (ie, chronically elevated serum insulin at the root of heart disease, type 2 diabetes and obesity). And in those over 60 years, a recent systematic review concluded that LDL cholesterol is not associated with cardiovascular disease and is inversely associated with all-cause mortality.8 A high TC to HDL ratio drops rapidly with dietary changes such as replacing refined carbohydrates with healthy high fat foods. [emphasis added]"

    Thus it is not fat and cholesterol that cause cardiovascular disease, but rather refined carbohydrates.  This is the paradigm shift that is occurring in the understanding of this and many other chronic diseases of modernity. 

    Normally, LDL cholesterol (the so-called 'bad' cholesterol) is big, buoyant and 'fluffy', and cannot get deposited into the walls of arteries.   However, with chronically elevated blood sugar due to insulin resistance, LDL cholesterol becomes oxidized, which makes it small, dense and hard. 

    This oxidized LDL cholesterol gets deposited into arterial walls, and triggers the chronic inflammation that leads to the formation of plaques in the arterial wall that is the hallmark of coronary artery disease (CAD).  CAD is not caused by fat and cholesterol "clogging the arteries":

    "The inflammatory processes that contribute to cholesterol deposition within the artery wall and subsequent plaque formation (atherosclerosis), more closely resembles a ‘pimple’ (figure 1). Most cardiac events occur at sites with <70% coronary artery obstruction and these do not generate ischaemia [blockage] on stress testing.4 When plaques rupture (analogous to a pimple bursting), coronary thrombosis [blood clotting] and myocardial infarction [heart attack] can occur within minutes."

    Excess consumption of refined carbohydrates, which leads to insulin resistance by the mechanism described above, and the damage that comes with chronically elevated blood sugar that results from insulin resistance (glycation, oxidation and inflammation), are the root cause of the chronic diseases of modernity.  Insulin resistance caused by the over-consumption of refined carbohydrates is the scourge of our time.

    The best way to combat this scourge is simple (but not necessarily easy):  reduce refined carbohydrates in your diet, exercise regularly, and reduce stress in your life:

    "And just 30 min of moderate activity a day more than three times/week significantly improves insulin sensitivity and helps reverse insulin resistance (ie, lowers the chronically elevated levels of insulin that are associated with obesity) within months in sedentary middle-aged adults. This occurs independent of weight loss and suggests even a little activity goes a long way.

    Another risk factor for CHD is environmental stress. Childhood trauma can lead to an average decrease in life expectancy of 20 years. Chronic stress increases glucocorticoid receptor resistance, which results in failure to down regulate the inflammatory response. Combining a complete lifestyle approach of a healthful diet, regular movement and stress reduction will improve quality of life, reduce cardiovascular and all-cause mortality.10 It is time to shift the public health message in the prevention and treatment of coronary artery disease away from measuring serum lipids and reducing dietary saturated fat. Coronary artery disease is a chronic inflammatory disease and it can be reduced effectively by walking 22 min a day and eating real food. There is no business model or market to help spread this simple yet powerful intervention."

    The following supplements may help to reduce the chronic inflammation that results from insulin resistance, but they are not a substitute for exercising regularly; eating real food and reducing refined carbohydrates in your diet; and reducing stress in your life.

    EPA and DHA Omega-3 Fatty Acids

    The omega-3 fatty acids (FA) are an essential group of nutrients that must be obtained from the diet.  The liver can convert the omega-3 FA alpha-linolenic acid (ALA) -- found in seeds, nuts and vegetable oils -- into eicosapentaenoic acid (EPA), and from EPA into docosahexaenoic acid (DHA), but only very inefficiently

    The best dietary sources of EPA and DHA are oily fish such as salmon, sardines and mackerel, or algae and plankton.  In the US and in many parts of the EU, however, the most prevalent dietary form of omega-3 FAs is ALA; DHA and EPA are consumed in insufficient amounts.

    DHA and EPA have been and continue to be extensively studied for their ability to modulate inflammation. 

    Inflammation is the innate immune system's first-line response to infection or injury, and is characterized by redness, heat, swelling and pain.  These are the result of white blood cells, in particular neutrophils, rushing to the site of injury or infection to do their job to defend the body against the injury or infection.

    Omega-3 fatty acids, in particular EPA and DHA, are actively involved in the regulation of both the initiation and the resolution of inflammation. 

    In the initiation phase, EPA and DHA can act in an anti-inflammatory role, by regulating pro- and anti-inflammatory signaling molecules (cytokines and chemokines), and by modulating gene activity involving nuclear factor-kappa B (NF-κB).

    In the resolution, or healing, phase, it has been discovered in the past 20 years that EPA and DHA are precursors to the molecules actively involved with and necessary for the successful resolution of inflammation, known as Specialized Pro-resolving Mediators (SPM).  A number of these SPM have been identified:  resolvins, protectins and maresins.

    These inflammation-resolving SPMs are relevant not only to acute infection and injury, but to many chronic diseases as well, because these have chronic inflammation as their underlying characteristic:  for example, cardiovascular diseases, metabolic syndrome, autoimmune diseases, and neuro-cognitive diseases.

    Thus EPA and DHA may be beneficial both for recovering from acute infection or injury, and for healing many chronic conditions involving underlying unresolved inflammation.

    Indeed, in cardiovascular disease, medical research has established that:

    Ubiquinol (CoQ10)

    Coenzyme Q10 (CoQ10) is a co-factor molecule found in every cell of animal tissue that performs aerobic respiration.  It is an integral component of the Electron Transport Chain found in mitochondria, the parts of cells that convert food and oxygen into adenosine triphosphate (ATP), the form of energy that cells require to function. 

    Although CoQ10 is found in all organs of the human body, it is most densely concentrated in tissue that has the highest energy requirements:  the brain, heart, liver and kidneys.

    CoQ10 is synthesized by the body and can be gotten in small amounts from food, primarily from fatty fish and meat.  The human body synthesizes less and less CoQ10 as it ages, in particular after the age of 40.

    In addition to its function as an electron carrier in the Electron Transport Chain in mitochondria, CoQ10 is a potent antioxidant in the reduced and oxidized forms in which it exists within cells:  ubiquinone is the oxidized form; ubiquinol the reduced form.  The ability of CoQ10 to exchange electrons with other molecules as it converts between its reduced and oxidized forms enables its antioxidant properties.

    CoQ10 has shown benefit over decades of studies in numerous cardiovascular diseases and the risk factors associated with them, as a recent systematic review outlines:
    • Reduction of Hypertension:  "CoQ10 seems to exert a direct effect on the endothelium, provoking vasodilation and lowering blood pressure [,]. This effect is linked to its ability to improve nitric oxides bioavailability and to induce vasodilatation especially in patients with hypertension."
    • Protection against oxidation of lipids:  "In human endothelial cells, the exposure to CoQ10 is associated with... reduction of the ROS [reactive oxygen species]-induced endothelial damage []. In fact, the main effect of CoQ10 on plasma lipids seems to be the increased LDL resistance to oxidative stress []."
    • Reduction of systemic inflammation:  Inflammation is the main process underlying cardiovascular disease.  CoQ10 significantly reduces the markers of systemic inflammation, such as tumor necrosis factor alpha (TNF-α) and C-reactive protein.
    • Protection against Heart Failure (HF):  HF is defined as "any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood."  Cardiac tissue is among the most energy-intensive tissues of the body, with high mitochondrial activity.  CoQ10 is essential to the process by which mitochondria produce energy.  Thus, it is not surprising that CoQ10 was found in patients with moderate to severe HF to reduce Major Adverse Cardiac Events, cardiovascular and all-cause mortality, and hospitalizations.
    • Protection against scarring and loss of left ventricular (LV) function after heart attack:  CoQ10 was found to reduce scarring and loss of LV function after heart attack, because it is "an ATP-sparing agent and regenerable antioxidant capable of protecting cell structures from oxidative damage during ischemia and reperfusion injury [,]."
    • Reduction of Atrial Fibrillation (arrhythmia in patients with HF or ischemic heart disease caused by blocked vessels):  Again, because of CoQ10's central role in the production of ATP and its ability to block oxidative damage by ROS, patients on CoQ10 are far less likely to develop atrial fibrillation.
    • Prevention of Ischemic stroke (IS) (stroke caused by blocked blood vessels) and damage following IS:  Pre-treatment with CoQ10 can reduce the incidence of stroke, and treatment after ischemic stroke with CoQ10 increases measures of cognitive and physical function.
    • Prevention of insulin resistance:  Mitochondria seem to play a key role in the development of insulin resistance; they are among the cell's insulin signalling mechanisms that get disrupted by the presence of excess fatty acids due to the overconsumption of refined carbohydrates.  As insulin resistance progresses, mitochondria produce more pro-oxidants (ROS).  CoQ10 supplementation can significantly improve measures of insulin resistance and provide antioxidant protection for mitochondria.
    • Protection against non-alcoholic fatty liver (NAFLD):  The exact mechanism of the development of NAFLD is not yet known, but it seems to involve dysfunction of liver mitochondrial cells.  CoQ10 can restore mitochondrial function and also help break down fat accumulation in the liver.  NAFLD patients on CoQ10 supplementation have been found to have significantly reduced markers of liver inflammation and fat accumulation.
    The form of CoQ10 at Support Protocols is the patented Kaneka QH Ubiquinol™, which is a fully reduced form of CoQ10 that is much more bioavailable than the cheaper, more commonly available ubiquinone form of CoQ10.

    Vitamin D, Magnesium and Boron:  Nutritional Triumvirate

    Vitamin D is among the most powerful of micronutrients, being involved in the cell signaling of nearly every system in the body.  For its active metabolite form in the body, calcitriol, it is more accurate to state that vitamin D is a hormone rather than a vitamin. 

    We saw above that coronary artery disease (CAD) is fundamentally a disease of inflammation, in which arterial plaques form due to the depositing of small, hard, oxidized LDL cholesterol particles in the arterial wall.  Inflammation is the front-line response by the immune system to injury or infection.

    The majority of immune cells have vitamin D receptors, reflecting the critical role that vitamin D plays in immune function:  vitamin D both strengthens the innate immune system to fight off infection by viruses and bacteria, and regulates the adaptive immune system to control inflammation and keep it from running amok.

    Cardiovascular cells also have vitamin D receptors, and experimental models have shown that vitamin D plays a key role in preventing the development of CAD, by down-regulating pro-inflammatory signaling molecules TNFα, IL-6, IL-1, IL-8, nuclear factor-κB (NF-κB), and C-reactive protein (CRP). 

    Vitamin D also helps maintain healthy blood vessel tone, and thus normal blood pressure.  High blood pressure is a risk factor for CAD.

    Magnesium:  Less well-known is magnesium's role in health:  it is involved in over 600 enzymatic reactions in the body, and is critical to heart, brain and musculoskeletal health.  It is difficult to get from the diet, and 60% or more of the population is estimated to be deficient in magnesium.  Magnesium modulates cellular reactions controlling inflammation and immune responses in the body -- a deficiency of magnesium will lead to increased inflammation and an over-reaction in immune responses.

    In heart muscle and blood vessels, in particular, magnesium:

    • Is essential for maintaining proper metabolic function, electrical activity and contraction of the myocardium;
    • Exerts an anti-inflammatory, antioxidant and vasodilating effect;
    • Reduces platelet aggregation and thus the risk of clotting after the bursting of an atherosclerotic plaque;
    • Therefore low magnesium levels have been shown to be associated with an increased risk of coronary artery disease (CAD);
    • Additionally low magnesium levels are associated with increased risk of acute myocardial infarction;
    • Low magnesium is also linked with high blood pressure;
    • Magnesium, because of its physiological role as a calcium antagonist, reduces vascular calcification, a common cause of cardiovascular death in patients with chronic kidney disease
    Boron helps the body to use vitamin D; aids in the absorption of magnesium; works with magnesium to retain calcium in bone where it belongs and out of soft tissue; works with both vitamin D and magnesium to reduce inflammation; raises levels of antioxidants such as glutathione; and aids in wound healing. 
    Boron deficiency has become widespread due to modern industrial agriculture, fertilizer use, and the depletion from topsoil of minerals essential to human health.
    Because of the essential role that vitamin D, magnesium and boron play in the regulation of calcium metabolism in the body, all three likely have a key effect in the prevention of the calcification that is involved in the formation of arterial plaque.

    Vitamin D, magnesium and boron should be thought of as the three co-essential members of a nutritional triumvirate, and should be taken together.

    L-arginine, nitric oxide precursor

    In the past 30 years, it has been discovered that nitric oxide (NO) is the Endothelium-Derived Relaxing Factor (EDRF), the molecule that causes vasodilation.

    L-arginine, a conditionally necessary amino acid, is the principal metabolic precursor to nitric oxide.  The body makes insufficient amounts of l-arginine, so it must be obtained in the diet.  L-arginine is found in red meat, poultry, fish and dairy foods. 

    Because of its role in nitric oxide production, l-arginine may:

    • Reduce hypertension, a key risk factor in cardiovascular disease;
    • Improve blood flow in peripheral vascular disease;
    • Reduce erectile dysfunction, which often correlates with cardiovascular disease;
    • Reduce chest pain due to coronary artery disease (angina)

    L-Carnitine, fatty acid transporter into mitochondria

    L-carnitine is another conditionally necessary amino acid, whose function is to transport fatty acids into mitochrondria so that they can be converted into energy.  The body can make small amounts of l-carnitine, but it must be obtained in the diet.  The most abundant source of l-carnitine is red meat.

    L-carnitine has numerous beneficial health effects: 

    Statin considerations: what actually causes coronary artery disease?

    We saw above that fat and cholesterol by themselves are not the cause of coronary artery disease (CAD), and that the model of CAD which sees it as fat and cholesterol 'clogging the pipes' is flat-out wrong.

    Cholesterol that becomes oxidized (small, hard, dense LDL particles) by chronically elevated blood sugar resulting from insulin resistance, and which subsequently gets deposited into arterial walls, is the beginning of CAD.  Preventing and reversing insulin resistance, reducing oxidation and preventing chronic inflammation from taking hold are the key to preventing CAD.

    So what causes high cholesterol?  How do statins work to reduce cholesterol, and does using them have any downsides?  Is it necessary to reduce cholesterol at all?

    To begin to address these topics, can eating 'too much' cholesterol raise your blood cholesterol?

    "Yes, but only if your body needs more cholesterol.

    The cells lining the small intestine each contain transporter molecules (NPC1L1) that absorb cholesterol. .... However, if the body doesn’t need any more cholesterol, there are other molecules (ABCG5/8 transporters) that pump the cholesterol right back out into the intestines to be eliminated from the body. This is one reason why it is virtually impossible for cholesterol from food to cause “high cholesterol.” The intestinal cells know exactly how much is needed and will not allow extra to be absorbed."

    If eating cholesterol cannot cause high cholesterol, then what does?  For approximately 0.5% of the population a genetic disorder called familial hypercholesterolemia (FH) results in an inability to regulate LDL cholesterol.  These people are born with high LDL cholesterol, which only continues to get higher as they age.  People with FH cannot control their high cholesterol with diet and exercise alone; they need medical treatment.

    What about those with "high cholesterol" who do not have FH -- how does their cholesterol get too high if it not by eating too much cholesterol?  Here insulin resistance rears its ugly head again, as we will see.

    All of our cells can make cholesterol from fat, protein and glucose, because cholesterol is an essential molecule for life.  

    "Life without cholesterol would be impossible. Cell membranes, which wrap around and protect the inner contents of all cells, must contain cholesterol in order to function properly. Cholesterol contributes firmness to membranes and keeps them from falling apart. But wait, there’s more!

    All of the following critical body components are made from cholesterol:

      • Estrogen
      • Testosterone
      • Progesterone
      • Cortisol (anti-inflammatory stress hormone)
      • Aldosterone (regulates salt balance)
      • Vitamin D
      • Bile (required for fat and vitamin absorption)
      • Brain synapses (neurotransmitter exchange)
      • Myelin sheath (insulates nerve cells)"

    The liver, in particular, is good at making cholesterol, and is the only organ that can make more than it needs for its own cells and ship it out to the rest of the body.   

    Making cholesterol is a complex chemical process which requires more than 30 steps.  Step 3, involving an enzyme called HMG-CoA reductase is the crucial step; once that step is reached, there is no going back -- cholesterol will be made.

    This is where insulin, and insulin resistance, come in, because what regulates HMG-CoA reductase are cholesterol levels in the body, and insulin.  The higher the level of insulin, the more HMG-CoA reductase the liver will make.

    Recall that insulin not only allows glucose inside cells, it regulates growth by controlling what the liver does with glucose.

    Cholesterol is needed to make new cells, so insulin signals the liver to make more of it when it senses that growth is occurring.

    With insulin resistance due to excess consumption of refined carbohydrates, however, the liver gets a false signal.  The repeated cycle of chronically elevated blood sugar and insulin levels causes the liver to commit to making more cholesterol than is actually needed by the body.

    Just as insulin resistance causes the liver to make excess triglycerides, it also causes the liver to make excess cholesterol, and ship both out to the rest of the body.

    How do statins reduce cholesterol?  They inhibit HMG-CoA reductase, which occurs very early in the 30-step metabolic pathway that makes cholesterol.  But this same metabolic pathway, known as the mevalonate pathway, is also responsible for making CoQ10, the steroid horomones (sex hormones and corticosteroids) and vitamin K, all things that our body needs for health and proper function.  

    We saw above that CoQ10 is an essential co-factor that enables mitochondria to produce cellular energy, and is also a potent antioxidant.  Thus, since statins reduce CoQ10, the adverse events associated with statins have at their core mitochondrial dysfunction and the consequences of reducing cholesterol levels to below what the body needs:  muscle pain, and in the extreme, muscle break-down; frailty; and cognitive dysfuction and dementia.

    Cholesterol levels should not be the therapeutic target of drugs and other agents to treat and prevent coronary artery disease.  As we saw above, our body knows how much cholesterol it needs:  it will intake and make exactly how much cholesterol it needs, and not more -- unless it is given a false signal by insulin resistance.

    Indeed, statins, by lowering cholesterol, do not decrease all-cause mortality in individuals without familial hypercholesterolemia or established coronary artery disease (1, 2, 3).

    The actual target of lifestyle and therapeutic interventions for coronary artery disease should be insulin resistance, because elevated blood sugar and insulin levels are what cause the oxidation and inflammation that result in arterial plaques, and elevated LDL cholesterol levels.