Understanding the Cholesterol Skeptic

A Crash Course in Understanding Lipoprotein Metabolism:

Lipoproteins are transporter molecules for cholesterol, fat and other fat soluble nutrients like vitamins A, K, D and E from the blood to different organs (liver) and tissues (adipose and other cells).  Cholesterol like all the other fats and fat-soluble vitamins are not water-soluble and do not dissolve in the blood, hence the requirement to be carried in “packages” called lipoproteins.  Lipoproteins consist of the following parts:

  • A core of fats (triglycerides), cholesterol esters (cholesterol linked to fatty acids), and fat-soluble vitamins.
  • A monolayer membrane of phospholipids and small amounts of free cholesterol.
  • Proteins called “apoprotein” which may be “integral” apoproteins (apoA or apoB) penetrating as a transmembrane protein through the monolayer membrane, compared to the “peripheral” apoproteins (apoC or apoE) that are on the outer surface of the phospholipid membrane.

Apoproteins are named according to their protein density for example “high density lipoprotein” (HDL) has high density protein and “low density lipoprotein” (LDL) contains low density protein.  There are 5 distinct lipoproteins:

  • Chylomicrons
  • VLDL (very low density lipoproteins)
  • IDL (intermediate density lipoproteins)
  • LDL (low density lipoproteins)
  • HDL (high density lipoproteins)

Each lipoprotein contains a specific content of protein, triglyceride, cholesterol and cholesterol ester (see table).

























Cholesterol ester






As you can see from the table the large chylomicron molecules and VLDL are the main carriers of triglyceride in our blood compared to the IDL, LDL and HDL molecules carrying predominantly cholesterol ester.  Remember from my previous blog on “fats” that triglyceride molecules consist of one glycerol molecule attached by an ester bond to 3 fatty acid molecules.  Triglycerides form the basis of our energy stores of fatty acids and may provide fuel for beta-oxidation to generate ATP (energy).

Cholesterol esters are simply cholesterol esterified to one fatty acid molecule and is essentially the mechanism by which cholesterol is transported around the body to various cells for the important use in cell membranes (with poly unsaturated fatty acids and saturated fatty acids).  The integrity and stability of cell membranes is entirely dependent on the relative content of these fatty acids and cholesterol.  Cholesterol is also the precursor of many very important hormones including Cortisol, Aldosterone, Testosterone and Estrogen, all vital to optimal health.

Chylomicron metabolism:

Chylomicrons are the lipoprotein packages transporting fat from our diet to adipose tissue in our body and the liver.  Our intestines package cholesterol, fats, and fat-soluble nutrients and vitamins into chylomicrons in the enterocyte cell lining the small intestine. The apoprotein that these lipoproteins get is apoB-48. It is an “integral” apoprotein (transmembrane protein) and is a shortened form of apoB-100, being approximately 48 percent as long.

The chylomicron is a very large molecule with the typical phospholipid and cholesterol monolayer with aopB48 and in the core of the chylomicron mostly triglycerides (see table above). 

Chylomicrons enter the lymphatic circulation and make their way via the thoracic lymph duct to the circulation where the duct empties into the subclavian vein in the neck. 

In the blood stream the chylomicrons acquire two new apoproteins, both peripheral apoproteins; apoC and apoE.  The chylomicrons travel either to the liver or adipose tissue.  In the liver the hepatocytes binds the apoE on chylomicrons via the LDL receptor (LDL-R) on the surface of the hepatocytes and the chylomicron is taken into the liver cell where the triglycerides will be used in metabolism.  The chylomicron will also bind preferentially to adipocytes via the apoC lipoprotein to lipoprotein lipase (LPL) an enzyme on the surface of the adipocyte.  The LPL cleaves the triglycerides in the chylomicron and the glycerol and free fatty acids enter the adipocyte thus depleting the chylomicron of triglyceride content and filling the fat cell with fatty acids.  When triglyceride is reduced to ~ 20% in the chylomicron the apoC dissociates from the chylomicron and this reduced triglyceride lipoprotein with only apoB48 and apoE is now called a “chylomicron remnant”. 

The chylomicron remnant is cleared from the circulation by the liver cell (hepatocytes) via the chylomicron remnant receptor on the hepatocytes, binding to the apoE on the remnant particle.  The liver then makes use of the remaining triglyceride.

VLDL, IDL and LDL metabolism:

VLDL lipoproteins are made by the liver for the purpose of transporting fat from the liver to other tissue especially adipose tissue. VLDL carries mainly triglyceride and cholesterol ester (see table above) and the each VLDL containing one apoB100 integral apoprotein in the monolayer membrane.

The VLDL passes into the blood stream and like chylomicron acquires two further apoC and apoE surface apoproteins actually obtained from HDL molecules.  Again identical to chylomicrons the VLDL binds the adipocyte via the apoC to LPL on the adipocyte with the enzyme cleaving the triglyceride to glycerol and fatty acids to be used by the adipocyte. 

As the triglyceride in the VLDL drops to 50% the VLDL dissociates from the LPL and returns to the liver binding to the LDL-receptor (LDL-R) via the apoE on the VLDL.  If the VLDL attached to the adipocyte stays attached longer or attaches to another adipocyte and depletes the triglyceride to 30% the lipoprotein becomes an IDL molecule which is triglyceride depleted and thus has more percent cholesterol ester.  The IDL is taken up by the liver by the LDL-R via apoE.  IDL can also rebind to adipocytes to deplete itself more of its triglyceride to ~ 10% where the IDL loses the apoE and apoC peripheral apoproteins and becomes a cholesterol ester rich LDL molecule with only one apoB100 apoprotein per LDL molecule.  So LDL looks similar to VLDL with a single apoB100 apoprotein but unlike the VLDL that is triglyceride rich the LDL is cholesterol ester rich and is the MAIN carrier lipoprotein to transport cholesterol via its ester to the liver and other cells throughout the body. 

Importantly the LDL molecule does not have apoE or apoC and is therefore not cleared from the blood by the liver as the LDL-R has high affinity for the apoE.  The apoB100 in LDL has a much lower affinity for the LDL-R on the hepatocytes and as a result the ½ life of LDL in the blood is much longer than all the other lipoproteins like VLDL; IDL both of which have apoE to bind the LDL-R on the liver cell.

The consequence of the long ½ life of LDL in the plasma is the LDL is susceptible to oxidative modification of the phospholipid monolayer containing polyunsaturated fatty acids. 

This is where the MISNOMER arises with LDL labelled as the “BAD” cholesterol. LDL is just the main carrier of cholesterol required by all cells in the body.  It is NOT the cholesterol that is atherogenic (causing atherosclerosis), it is the damaged oxidized LDL lipoprotein that is taken up by macrophages in the sub endothelial space of the arterial lining. 

The problem is that LDL is our carrier of cholesterol and so high LDL particularly when oxidized is directly associated with high risk for vascular disease.

A word on HDL metabolism:

HDL is the lipoprotein transporting cholesterol from the tissues back to the liver for excretion into bile for elimination in the bowel but in the small bowel 70% of cholesterol excreted ultimately is reincorporated with diet fat into chylomicrons in the enterocyte to begin the whole process again. 

HDL is synthesized by the liver cells (and other gastro intestinal cells) and is a unique lipoprotein containing one integral transmembrane apoA apoprotein.  HDL when synthesized has very little triglyceride or free cholesterol and is essentially “empty” as its job is to acquire cholesterol from the periphery to transport back to the liver.  In the circulation the empty HDL acquires an enzyme LCAT (lecithin-cholesterol-acyltransferase).  The HDL with LCAT imbedded in its monolayer membrane attaches to any cell binding to the cholesterol esters in the outer layer of the phospholipid bilayer cell membranes and the LCAT attaches to the Hydroxy group on the cholesterol ester and extracts the ester from the outer cell membrane into the HDL molecule.  Thus HDL takes cholesterol from peripheral cells and loads the cholesterol ester into the HDL and transports this back to the liver attaching to the apoA-receptor on the liver cell for the cholesterol to be synthesized in bile.

So in deficient HDL (low HDL) states there is less of this carrier molecule to unload the cells and arterial wall of cholesterol content hence an independent risk for vascular disease.  Like LDL you can equally understand the MISNOMER of HDL being “good cholesterol” as low levels potentiate vascular disease whilst high HDL tends to protect against atherosclerosis BUT it is NOT cholesterol that is implicated; it is the carrier molecule HDL. 

Cholesterol is cholesterol and is a fat for cell membrane integrity, stability and synthesis of steroid hormones.  However with cholesterol’s association with the carrier molecules it is NECESSARILY implicated in vascular disease.  Just as smoke is a marker of a fire; smoke is not the cause of fire but the presence of lots of smoke necessarily suggests a nasty fire?

So now you understand the whole lipoprotein story………..

How do LDL and HDL Affect Atherosclerosis?

To clarify:

LDL (the main cholesterol rich) lipoprotein and if it spends too long in the circulation by poor hepatic uptake tends to oxidize. The polyunsaturated fatty acids (PUFA) in its membrane get damaged by free radicals, and then they proceed to damage the protein in the surface, and finally the fatty acids in the core.

Once LDL oxidizes, it can invade the arterial wall in areas that experience disturbed blood flow (turbulence), like the points where arteries curve or branch. These areas are permeable to large molecules. Oxidized LDL attracts immunocompetent white blood cells (to repair the artery) and initiate an inflammatory cascade that produces the unstable arterial plaque.  This is the basis of the “oxidized LDL theory of atherosclerosis”.

Much has been made of the “reverse cholesterol transport” mechanism whereby HDL extracts cholesterol from arterial plaques, but HDL has other importance roles in atherosclerosis with its antioxidant and anti-inflammatory properties key to the protective effect of HDL.

What is Lipoprotein “a” or Lp(a)?

Lipoprotein “a”, often abbreviated Lp(a), is essentially a subset of LDL. Lp(a) is a strong and independent risk factor for atherosclerosis and is found in arterial plaque. One hypothesis put forward in the late 1980s suggested that Lp(a) promotes blood clotting by inhibiting an enzyme that breaks down clotting factors.

More recent research has shown that virtually all the LDL containing oxidized phospholipids in the blood is associated with Lp(a). Moreover, oxidized LDL transfers oxidized phospholipids from its membrane directly to the Lp(a) particle. Thus, Lp(a) appears to be a marker for oxidation of the LDL membrane, although it is possible that Lp(a) also picks up oxidized phospholipids from the membranes of cells, such as the endothelial cells that line the blood vessel wall.

The Importance of the LDL Receptor (LDL-R) to Vascular Disease

We have seen from my previous dialogue the longer LDL remains in the circulation and not cleared by the LDL receptor the more chance the LDL has of undergoing oxidative modification to become atherogenic.  So clearly there would be MULTIPLE mechanisms of increased risk for atherosclerosis:

  • Having too much LDL in your blood stream by simply “overloading” the delicate lipoprotein cycle.  We see this practically in obesity and metabolic syndrome where a constant release of fatty acids in the circulation from adipose tissue is expressed by high plasma triglyceride content; increased LDL; increased VLDL and IDL and low HDL.  
  • Having high oxidative stress within the circulation seen in smokers; obesity and metabolic syndrome; lack of physical exercise and cardiovascular conditioning; diets high in TRANS-fats and oxidized polyunsaturated omega-6 fats; diets low in omega-3 fats and natural whole food antioxidants; hypertension and diabetes.
  • Having too little LDL-R number or activity (familial hypercholesterolaemia and PCKS9 gene alterations).  If LDL receptors are missing/defective as in familial hypercholesterolaemia or down regulated by the action of the PCKS9 gene the LDL is not cleared from the circulation allowing more time for the LDL to undergo oxidative modification and damage to the arterial wall.  Defective apoB100 lipoproteins on LDL can cause poor LDL-R uptake even if the LDL-R is normal.  On the other hand, people with genetic defects in the PCSK9 gene leading to up-regulation of the LDL-R have a greatly reduced risk of heart disease. Two percent of African-Americans have a mutation that deletes the PCSK9 gene product, an enzyme that would under normal circumstance degrade the LDL-R.  Those individuals possessing this mutation have an 88 percent reduced risk of heart disease. This constitutes an almost complete abolition of heart disease over their lifetime.
  • LDL production is influenced by other hormone systems, and contributes to elevation and oxidative damage to the LDL. Low levels of Thyroid hormone (hypothyroidism); high estrogen levels (obesity/ metabolic syndrome) and elevated glucocorticoid hormone (people taking Prednisone) is associated with high LDL.

So to Summarize:

  1. You can see why TOTAL cholesterol in the blood measured during a lipogram is a poor predictor for heart disease.
  2. You now understand that LDL is the molecule that is pivotal to the initiation of atherosclerosis and that the attempt to heal the damage to the artery mediated through the immune system actually causes an inflammatory cascade potentiating the development and instability of the plaque.
  3. As LDL is the MAJOR carrier of our cholesterol, a measure of high LDL as LDL-cholesterol, is a very powerful determinant of vascular disease.
  4. This is compounded by the clinical states with low HDL syndromes.
  5. Elevated blood triglyceride is usually accompanied by high levels of VLDL and IDL although these are not measured in a lipogram.  You will see that in the setting of high triglyceride the HDL is often low and so if you subtract the HDL from the total cholesterol you are left with the “non-HDL” fraction.  The represents ALL the atherogenic lipoproteins (LDL + IDL + VLDL) and is an excellent predictor for vascular disease.
  6. As more and more oxidation of LDL occurs and the LDL molecule becomes smaller and dense (so-called B-pattern of LDL) compared to the A-pattern of LDL (buoyant unoxidized fluffy large LDL).  Pattern A is minimally atherogenic compared to the highly atherogenic B-pattern. 
  7. A particularly GOOD way of assessing your “total” atherogenic risk is to ask the lab for an apoB level as this reflects your total atherogenic burden from all the apoB containing lipoproteins (LDL + VLDL + IDL).
  8. Statins work by switching off the rate-limiting step of cholesterol synthesis in hepatocytes thus decreasing the amount of cholesterol in the liver cell.  The cell is led to believe it is deficient in cholesterol and therefore up-regulates the LDL-R on the surface of the cell to remove more LDL from the circulation to boost the intracellular cholesterol.  Circulating LDL is removed thus shortening the plasma ½ life making oxidative damage less.
  9. PCSK9 inhibitors also increase the expression of LDL-R allowing better plasma clearance of LDL accounting for lower plasma LDL and thus less cardiac risk.
  10. Ezetimibe works by blocking the absorption of cholesterol uptake at the brush border of the enterocyte and thus reduces the total available cholesterol and cholesterol ester to be incorporated into chylomicrons which ultimately lead to less LDL via a knock-on effect.

So I guess the cholesterol skeptic has good foundation for their belief but they are misguided to suggest the “lipid theory of atherosclerosis” is nonsense. 

Way back in 1913 Nikolai N. Anichkov (1885-1964) demonstrated the role of cholesterol in the development of atherosclerosis. His classic rabbit experiments paved the way to our current understanding of the lipid theory of atherosclerosis with Anichkov’s research often cited amongst the greatest discoveries of the 20th century.

Perhaps the most striking finding reflecting back on Anichkov’s work was that if you fed rabbits a diet high in cholesterol the rabbits promptly developed atherosclerosis.  Anichkov injected intravenously, rabbits with cholesterol only to find no atherosclerosis indicating the role of what we know today with the role of lipoproteins packaging and carrying cholesterol.  A later group of scientists (Gofman’s group) confirmed that Anichkov was correct but they did something that Anichkov could not have done in 1913-they developed and used an ultracentrifuge capable of rotating its tubes 40,000 times per minute. The hypercholesterolaemic serum samples of their cholesterol-fed rabbits were centrifuged and then sequestered into 2 distinct compartments. The 1st fraction was designated low-density lipoprotein (LDL) cholesterol, because it floated toward the surface of the serum sample. The 2nd fraction was deposited at the bottom and was designated high-density lipoprotein (HDL) cholesterol. Gofman’s group showed that injecting that low-density lipoproteins cholesterol into rabbits and a host of other animals caused rapid development and progression of atherosclerosis.

What are the Practical Implications for You?

  1. Undergo cardiovascular risk stratification annually to assess your global risk for vascular disease.
  2. Document your LDL; HDL and calculate your non-HDL as a baseline and see whether you are Lipoprotein “a” positive or negative.  If  you are Lp “a” + you need to be even more aggressive with LDL reduction and HDL elevation (to specified goal targets).
  3. Document your “ultrasensitive C-reactive protein (us-CRP) as a marker of your systemic (vascular inflammation) for if  > 1.0 mg/L then you need therapy to lower us-CRP to < 1.0 and to keep LDL < 1.8-2.5 and HDL > 1.2.
  4. Document your total “apoB” as a measure of your “total atherogenic lipoproteins” for if your LDL is low but apoB high then you likely have small dense atherogenic LDL and perhaps high IDL and VLDL as direct risk for atherosclerosis.
  5. Finally document you Omega-3 Index to ensure optimal (omega-3) fatty acid composition in your (red cell) membranes for cellular stability.


Proverbs 4:23

Above all else, guard your heart, for everything you do flows from it.



Good Fat bad Fat what’s going on?

What are fats?

Fatty acids are derived from triglycerides or phospholipids. When they are not attached to other molecules, they are known as “free” fatty acids. Fatty acids are important sources of fuel because, when metabolized, they yield large quantities of energy in the form of ATP. Many cell types can use either glucose or fatty acids for fuel to generate ATP. In particular, heart and skeletal muscle prefer fatty acids. The brain cannot use fatty acids directly as a source of fuel; it relies on glucose or ketone bodies a breakdown product of fatty acids.

A triglyceride (triacylglycerol) is an ester comprising one molecule of glycerol attached to three fatty acids.  We store our fat as triglyceride in fats cells and we eat fat as triglyceride in the form of animal fat, vegan or fish oils. There are many types of triglycerides: depending on the oil source and fatty acid composition.  The fatty acids are described according to their carbon length (6-22 carbon molecules) and whether the hydrocarbon is fully saturated with hydrogen molecules (saturated fat) or unsaturated where Carbon=Carbon molecules are joined by double bonds using sites where Hydrogen could be bound.  The presence of one double bond labels the unsaturated fatty acid monounsaturated fatty acid (MUFA) and if two or more double bonds are called polyunsaturated fatty acid (PUFA).

 Example of an unsaturated fat triglyceride:  Left part: glycerol; right part from top to bottom; palmitic acid; oleic acid; alpha-linolenic acid (formula C55H98O6)

Unsaturated fats are the main constituents of vegan oils (MUFA & PUFA) whereas animal fats tend to be more saturated.  The double bonds in the fatty acids increase vulnerability to “free radical” attack or oxidation and accounts for the rancidity of these types of fat in room air.  The double bonds also change the shape of the fatty acid and depending on “cis” or “trans” configuration makes the fatty acid bent, kinked and curved rather the densely packed saturated fatty acids accounting for the solid appearance at room temperature.


Monounsaturated fatty acids (MUFA) like oleic acid are considered healthy by conventional standards (rich in olive oil) but monounsaturated fatty acids also make up a big portion of animal fat, as much as 44% in pork lard, so it makes sense that we have evolved to process them. So if you want to increase monounsaturated FAs in your diet, fatty chunks of meat will get you much further than a tablespoon of olive oil on your salad.


Polyunsaturated fatty acids (PUFA) are subdivided into omega-3, omega-6 and omega-9 fats described by the position of their first double bond if you count from the methyl (or omega) end of the chain. The fatty acid with the first double bond in position 3 is therefore omega-3 PUFA and so on.

Animals do not tend to store large amounts of polyunsaturated fatty acids, mainly because they are not a very good source of energy. Therefore traditional animal fats are quite low in PUFA whilst fish; nuts; seeds and vegetable oil are rich in PUFA but differing amounts and content of omega-3, omega-6 and omega-9 PUFA. 

All PUFA (omega fats) tend to be lumped together in one big “healthy” basket (which is incorrect) as there are significant differences in their effect on the body.

The following table gives the fatty acid, vitamin E and cholesterol composition of some common dietary fats.

PUFA are not the body’s preferred fuel but rather form integral component of cellular membranes (for membrane stability), and are necessary for the synthesis of important cellular messengers called eicosanoids (hormones) controlling and initiating inflammation with other cytokine chemicals.  

PUFA are also involved in two of the most critical processes: oxidation and inflammation and whist both are essential to life, both are dangerous when they get out of control.  Omega-3 alpha-linolenic acid (ALA) and omega-6 linoleic acid (LA) are the two major components of the essential PUFA omega-3 and omega-6 family.


ALA taken in the diet is converted to eicosapentaenoic acid (20:5, n−3; EPA), and docosahexaenoic acid (22:6, n−3; DHA). These three polyunsaturated fats (ALA; EPA & DHA) are the typical omega-3 fats to which we refer

EPA concentration in our body is very low as it seems to be converted immediately to its brother DHA. Although EPA and DHA can be synthesized from ALA the conversion in our body is very inefficient for the rate of conversion for ALA to EPA is around 8%. That is out of 1 mg of ALA from flaxseed oil you will only make 0.08mg of EPA. DHA conversion rate is even poorer. It ranges from 0.5% in normal adults to 4% in young women. 

In other words we also need to take in natural EPA and DHA in our diet in various foods  for the important omega-3 benefits.

The health benefits of the long-chain omega-3 fatty acids — primarily EPA and DHA are the best known. These benefits were discovered in the 1970s by researchers studying the Greenland Inuit tribe who consumed large amounts of oily fish & other marine fat (omega-3) & displayed virtually no cardiovascular disease. The high level of omega-3 fatty acids consumed by the Inuit reduced triglyceride, heart rate, blood pressure and atherosclerosis.

By 1979, it seems the picture was clearer as the health benefits of omega fats were found to be due to a family of hormones now known as eicosanoids: Thromboxanes, protacyclines and leukotrienes. The eicosanoids, which have important biological functions, typically have a short active lifetime in the body, starting with synthesis from the omega fatty acids and ending with metabolism by enzymes. Researchers found that omega-3 fatty acids are converted into omega-3 eicosanoids in competition to the omega-6 eicosanoids formed from the omega-6 fat precursor Arachidonic acid (by the same enzymes).

The essential parent fatty acid in the omega-6 family is linoleic acid (LA) and is enzymatically converted to the omega-6 eicosanoids of the arachidonic acid family (pro-inflammatory) .

Arachidonic acid is a central player in the cascade of reactions which promote chronic inflammation and ill-health and disease if the ratio of omega-6: omega 3 intake is high due to important competitive interaction with the omega-3 fatty acids affecting the relative storage, mobilization, conversion and action of the omega-3 and omega-6 eicosanoid precursors. It seems the eicosanoids made from omega-3 fatty acids are produced more slowly and are often referred to as anti-inflammatory, but in fact they are just LESS inflammatory than those made from omega-6 fats.

The point is that if BOTH omega-3 and omega-6 fats are present they will “compete” to be transformed, so the ratio of long-chain omega-3: omega-6 fatty acids directly affects the type of eicosanoids that are produced (anti-inflammatory versus pro-inflammatory).

This competition seems to be the “hall-mark” of chronic degenerative inflammatory based disease (like atherosclerosis; Alzheimer’s dementia; macular degeneration; multiple sclerosis; auto-immune disease; cancer etc.).  These eicosanoids are a complex group of hormones recognized as important when it was found that thromboxane is a factor in the clumping of platelets, which can both cause death by thrombosis and prevent death by bleeding. Likewise, the leukotrienes were found to be important in immune/inflammatory-system response, and therefore relevant to arthritis,lupus, asthma and recovery from infections.

These discoveries have led to greater interest in finding ways to control the synthesis of omega-3 and omega-6 eicosanoids. The simplest way would be by consuming more basic omega-3 fatty acids and fewer omega-6 fatty acids in your diet.

Clinical studies indicate that ratio of omega-3 to omega-6 fatty acids is CRITICAL to maintaining optimal health and good aging with higher omega-3 contributing to the formation of the important omega-3 based eicosanoids such as prostoglandins, leukotrienes and thromboxanes, all tending to dampen down the immune based cascade of cellular and systemic chronic inflammation and thus alter the body’s metabolic function.

In general, grass-fed animals accumulate more omega−3 than do grain-fed animals, which accumulate relatively more omega−6. Remember metabolites of omega−6 based eicosanoids are more inflammatory (particularly arachidonic acid) than those of omega-3. This necessitates that omega−3 and omega−6 fats be consumed in a balanced proportion; healthy ratios of omega-3 to omega 6 range from 1:1 to 4:1 (an individual needs more omega 3 than omega 6). Studies suggest the evolutionary human diet, rich in game animals, seafood, and other marine sources of omega-3 would have provided such a ratio  (paleolithic man).

Typical Western diets have CORRUPTED this ratio to between 10:1 and 50:1 (i.e., dramatically higher levels of omega-6 than omega-3) due to the drastic introduction of vegetable oils: like sunflower oil (no omega-3 fats); cottonseed oil (almost no omega-3); peanuts and peanut oil (extremely high in omega-6); soybean oil (7:1 omega-6 to omega-3); grape seed oil (almost no omega-3) and finally corn oil (46:1 omega-6 to omega-3).

Canola oil tends to be better at (2:1 omega-6 to omega-3); olive oil 3:1 omega-6 to omega-3) and the BEST flaxseed oil (1:3 with more omega-3 than omega-6).

With the much higher ratio of omega-6: omega-3 in the so-called “neolithic” diets; blood triglycerides have been higher; rate of obesity and cardiovascular disease higher ; auto-immune disease and cancer rampant.

In 1999, the GISSI-Prevenzione Investigators reported in The Lancet the results of major clinical study in 11,324 patients with a recent myocardial infarction. Treatment 1 gram per day of omega-3 fatty acids reduced the occurrence of death, cardiovascular death, and sudden cardiac death by 20%, 30%, and 45%, respectively. These beneficial effects were seen from three months onwards.

In 2006 the American Journal of Clinical Nutrition and a second JAMA review; both indicated decreases in total mortality and cardiovascular incidents (heart attacks) associated with the regular consumption of fish and fish oil supplements.

In the March 2007 edition of the journal Atherosclerosis in 81 Japanese men with unhealthy blood sugar levels were randomly assigned to receive 1.8 g daily of EPA, with the other half being a control group. The thickness of the carotid arteries and certain measures of blood flow were measured before and after supplementation. This went on for approximately two years. A total of 60 patients (30 in the EPA group and 30 in the control group) completed the study. Those given the EPA had a statistically significant decrease in the thickness of the carotid arteries, along with improvement in blood flow. The authors indicated that this was the first demonstration that administration of purified EPA improved the thickness of carotid arteries and improved blood flow in patients with unhealthy blood sugar levels.

In a study published in the American Journal of Health-System Pharmacy March 2007, patients with high triglycerides and poor coronary artery health were given 4 grams a day of a combination of EPA and DHA along with some monounsaturated fatty acids. Those patients with very high triglycerides (above 4 mmol/l) reduced their triglycerides on average 45% and their VLDL cholesterol by more than 50%. 

Similar to those following a Mediterranean diet, Arctic-dwelling Inuit – who consume high amounts of omega-3 fatty acids from fatty fish also tend to have higher proportions of increased HDL cholesterol and decreased triglycerides and less heart disease. 

A study of 465 women showed that serum levels of EPA are inversely related to levels of anti-oxidized-LDL antibodies. As you are aware oxidative modification of LDL is thought to play a major role in the development of atherosclerosis through formation of unstable plaque.

Survivors of past heart attacks are less likely to die from an arrhythmia event if they are consuming high levels of omega-3 (membrane stabilisation). These antiarrhythmic effects are thought to be due to omega-3 fatty acids’ ability to increase the fibrillation threshold of the heart electrical and tissue.

Omega-3 fatty acids also have mild antihypertensive effects. When subjects consumed daily systolic blood pressure was lowered by about 3.5-5.5 mmHg and heart rate by 3-5 bpm.

In a study regarding fish oil published in the Journal of Nutrition in April 2007, sixty-four healthy Danish infants from nine to twelve months of age received either cow’s milk or infant formula alone or with fish oil. Those infants supplemented with fish oil were found to have improvement in immune function maturation, with no apparent reduction in immune activation.

Consumption of EPA partially countered memory impairment in a rat model of Alzheimer’s disease and produced a statistically insignificant decrease in human depression.

Flaxseed oil, walnuts, canola oil – all contain high level of ALA, the parent omega-3 molecule.

They are also promoted as equally good sources of omega-3 as fish and other marine products, which are rich in EPA/DHA. Meat, dairy and eggs (grass-fed and pastured) are also sources of omega 3 PUFA but unlike fish source or EPA and DHA, vegan, nut and seed ALA tend to go hand-in-hand with the omega-6 PUFA (LA) and this tends to upset the delicate omega-3: omega-6 balance.  So it is important to have a BASIC understanding of the CONTENT of omega-3 (especially whether EPA or DHA) versus omega-3 ALA and omega -6 LA in various foods.

The implications are particularly important for vegetarians and vegans as the omega-6; omega-3 ratio tends to heavily favour omega-6 PUFA (up to 50:1) and may contribute to ill-health.

Don’t be fooled by marketing as supplementing with “evening primrose” oil is pure omega-6 (LA).

Most of the processed pre-packaged food comes with a surprise high concentration of LA (omega-6) in form of soybean oil, sunflower oil, cottonseed oil, and peanut oil.  These oils were not around 200 years ago but ever since Ancel Keys published the (in)famous 7-Countries study (in the late 1960’s) implicating saturated fat as the villain causing heart disease and the subsequent diet decisions from the McGovern committee driving farming subsidies and industrialisation of food, everything that was processed, packaged, patented and promoted contained high proportion of omega-6 fatty acids in the modern “healthy” diet.

Many health products which contain nuts, peanut butter, seed trail mix, nut bars etc promoted for good heath actually backfired for although the nuts and seeds contained no saturated fat and little omega-3 fat; the problem is that there was an overwhelming load of LA contributing to the pro-inflammatory effects  and effectively shutting down the already-poor conversion of omega-3.  The trend of low-fat vegan diets over the past 50 years has exacerbated the unhealthy omega-6: omega-3 ratio!


Evolutionary clues should tell you that eating meat, fish, eggs, pastured dairy and some plants, seed & nuts will give you all the PUFA you need but nuts and seeds needs to be taken in small amount so as not to calorie or omega-6 overload.

Supplementing with daily omega-3 in the form of pure salmon oil is essential (2 g/d) but it is vital to ensure the integrity of the product.  Recently a SA study identified > 50% of the preparations available in SA contained < 90% of the active EPA/DHA advertised on the label.  This highlights the problem of poor regulation of the supplement industry and the need to document your Omega-3 Index of your red cell membrane to ensure adequate omega-3:omega-6 ratios. DO NOT take supplements that has Omega-6 or Omega-9 as this makes no sense when we are trying to correct the already high omega-6 to omega-3 ratio.

So in summary:

  1. Have a BASIC understanding of what fat is in terms of triglyceride; saturated fatty acids and unsaturated acids.
  2. Understand the concept of the essential polyunsaturated fatty acids (PUFA) of the omega-3 and omega-6 family.
  3. Realise that many “healthy” vegan low-fat options tend paradoxically to have HIGH omega-6 intake thus skewing the balance of omega-3 to omega-6 in your diet.
  4. If possible take your omega-3 in “whole foods” that are unprocessed (like fresh fish) rather that from supplement form or take a combination of the two
  5. Do not take omega-6 supplements
  6. Ultimately you have to know what the ratio of these PUFA are in your cellular membranes as you can actively address any deficiency.

I will devote the next blog to all the research available on the Omega-3 Index test looking at the fat content of the red blood cell (RBC) membrane in different population groups; different risk groups and the data we have available to South African’s.



Some New Ideas for the Cholesterol Skeptic

God’s World gives us some really good examples of “non-atherosclerotic” animal models. Many wild mammalian species exist with natural total cholesterol level of 2.0-2.5 mmol/l  (LDL-C levels around 0.8 to 1.8 mmol/l).   To convert mg/dL to mmol/l divide by 40.


Humans are born with LDL-C levels in this range, but the level gradually increases with age. At least 2 adult human populations, however, do not exhibit this progressive increase in LDL-C with age. One population consists of hunter-gatherer societies, diverse in geographic location and ethnic origin but arguably living the way humans did 40,000 years ago. LDL-C levels remain in the 1.0-1.8 mmol/l range. In modern societies, rural Chinese blood levels often fall within this range. In neonates and these 2 adult groups, atherosclerotic coronary disease is rare. The consistency of these diverse human data sources, taken together with the mammalian species data, supports the speculation that the putative NORMAL range of LDL-C in adult humans may be approximately 1.0-1.8 mmol/l and NOT ~ 3.0 as currently quoted.  The speculation being; that modern Man and Woman have corrupted this process (as seen in the graphic) with total cholesterol > 5.0 and LDL-C > 3.0.

Intravascular ultrasound (IVUS) imaging has demonstrated the extent of atherosclerosis in American youngsters. 

An incredible study was performed on 262 young people who died prematurely and whose hearts were being transplanted.  Just prior to the transplantation the coronaries of these “hearts” underwent  IVUS and images reviewed at 2,014 sites within 1,477 segments in 574 coronary arteries. Lesions with an intima thickness >0.5 mm were defined as atherosclerotic.

In this population, 52% had lesions, ranging from 17% in individuals younger than 20 years to 85% in those older than 50 years of age. In those with lesions, intima thickness averaged 1.1 mm and area stenosis was 33%. Data taken from a large number of age-stratified autopsy studies establish the fact that coronary atherosclerosis begins in youth. If many of these individuals are those destined to become those who compose the >50% mortality statistic, therapeutic lowering of the LDC-C to the putative normal range might LOGICALLY begin during this point in pathogenesis, provided that they can be accurately identified.

Two recent randomized clinical trials allow the next logical step: examining the effect of therapeutic LDL-C lowering into this putative normal range. In ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound), reduction of LDL-C from 3.2 mmol/l to 1.5 mmol/l (12% < 1.0 mmol/l LDL-C and 41% between 1.0 and 1.5 mmol/l) resulted in regression of carotid atherosclerosis using transvascular ultrasound. In JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin), reduction of LDL-C from 2.7 mmol/l to 1.4 mmol/l  in an asymptomatic intermediate-risk population resulted in a 44% reduction in adverse cardiac events to 1.4% in those with on-treatment LDL-C < 1.8 mmol/l. Neither trial identified increased statin-induced toxicity with CRESTOR 20 mg/d at lower on-treatment LDL-C levels.

These new data are supported by linear extrapolation of on-treatment LDL-C levels in both secondary angiographic and primary prevention trials. In the former, lesion progression reaches zero at an LDL-C of 1.7 mmol/l and coronary events reach zero at approximately 0.8 mmol/l. In primary prevention trials, major adverse cardiac events reach zero at an on-treatment LDL-C level of 1.4 mmol/l. Thus, to the lipid profiles in mammals, neonatal humans, and isolated human societies, we may add clinical trials that suggest the putative normal LDL-C level may be approximately 0.8 to 1.8 mmol/l.

If this is still not enough have a look at the “talk of the town this week”, as a paper has just been published in the New England Journal of Medicine describing a new gene importantly involved in regulation of the LDL receptor. This gene, PCSK9, codes for a secreted protease that acts to decrease the number of LDL receptors expressed in the liver cells. 

Plasma LDL is governed entirely by the number or LDL receptors; the rate at which the receptor binds apo-B100 in the LDL particle in the plasma (to clear the blood of LDL) and the recycling of the receptor back onto the cell membrane for re-use.

When PCSK9 binds the LDL receptor, it causes them to degrade. Individuals have been found with naturally occurring “loss-of-function mutations” in this PCSK9 gene causing increased expression of LDL receptors due to loss of function of PCSK9 and protection from heart disease due to very low LDL-C levels. This loss-of-function mutation occurs in 2% of African-Americans, with LDL-C levels naturally reduced by about 80%. This gets to the concept of another approach that could result in lifelong low LDL. Rather than hitting people late in life with intensive therapies (Statins), perhaps you could start earlier with more moderate reductions.

Over expression of the gene (or gain-of-function mutations) lowers LDL receptor number and thus raises plasma LDL levels; knocking out the gene (or a loss-of-function mutation) increases LDL receptor number and thus lowers LDL levels. 

The key point here is that the vascular disease in subjects with nonsense mutations in PCSK9 that cause low plasma LDL levels, presumably from birth resulted in an 88% reduced risk for vascular disease. Having a low LDL from birth almost triples the magnitude of the effect on risk compared with the risk reduction found in a 5-year trial of middle-aged people. Drugs that regulate the expression and function of PSCK9 have already been tested in early trials with staggering LDL-C reduction to the levels described above where atherosclerosis is reduced to ZERO (LDL 1.0 to 1.8 mmol/L) and may fairly soon join the ranks of cholesterol-lowering agents. Working by a different mechanism, PCSK9 inhibitors would probably have effects additive to those of other drugs like Statins.

So what am I saying?

Based on the information gathered over 3 decades of research it seems we need to keep our LDL around 1.0-1.8 mmol/l lifelong.  The longer and earlier we keep LDL-C at these putative NORMAL levels we will NEVER get vascular disease.  If you can’t do this with good lifestyle (exercise and diet) you need modern pharmacology to help you. 

Presently we only have Statins but with the potent, effective and safe Statins like Crestor, we are blessed we can influence LDL levels.

To help you make an informed decision you can be guided by transvascular ultrasound of your Carotid arteries.

This technology can define the state of your arteries and is extremely accurate in diagnosing “sub clinical” atherosclerosis.  If your arteries are entirely normal (smooth thin initima-media with no plaque)you can manage your cholesterol (LDL) profile more conservatively.

If you have any subclinical atherosclerosis then you are advised to lower LDL to the optimal level ~ 1.8 mmol/l to prevent progression to clinical disease and clinical cardiovascular events.

Please DON’T be complacent about your LDL-C level even if your HDL-C (good) cholesterol is preserved as I see many (Women) with great HDL levels but with LDL level above the putative optimal with Carotid arteries like the image above packed with atherosclerotic plaque, feeling well, asymptomatic and “healthy” and in some cases quite beautiful on the outside?