The Israeli Paradox

Diet and disease--the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet.

Yam D, Eliraz A, Berry EM.

Source

Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, Israel.

Abstract

Israel has one of the highest dietary polyunsaturated/saturated fat ratios in the world; the consumption of omega-6 polyunsaturated fatty acids (PUFA) is about 8% higher than in the USA, and 10-12% higher than in most European countries. In fact, Israeli Jews may be regarded as a population-based dietary experiment of the effect of a high omega-6 PUFA diet, a diet that until recently was widely recommended. Despite such national habits, there is paradoxically a high prevalence of cardiovascular diseases, hypertension, non-insulin-dependent diabetes mellitus and obesity-all diseases that are associated with hyperinsulinemia (HI) and insulin resistance (IR), and grouped together as the insulin resistance syndrome or syndrome X. There is also an increased cancer incidence and mortality rate, especially in women, compared with western countries. Studies suggest that high omega-6 linoleic acid consumption might aggravate HI and IR, in addition to being a substrate for lipid peroxidation and free radical formation. Thus, rather than being beneficial, high omega-6 PUFA diets may have some long-term side effects, within the cluster of hyperinsulinemia, atherosclerosis and tumorigenesis.

Understanding Body Fat

Having a good understanding of the actual physiology of body fat regulation, including how fat enters the body, how it is created within the body, how it gets stored, how you mobilise it, the best way to maximise its use, whilst minimising its storage above and beyond desirable levels, will put you one step ahead in your quest to control body fat. 

The progress of a fattening adipocyte

In order to maintain strength and survive times when food was not easily available, your body needed a clever, space-efficient way to store and carry plentiful supplies of energy.  We have a beautiful and ingenious solution to this physiological problem, it's called adipose tissue or body fat!


In the past, body fat was fundamental to survival and a highly desirable attribute.  Today you might think differently.  You possibly even hate your body fat, however your body and particularly your genetic blueprint is stuck in the past, and it loves your fat.  The body thinks your fat is so fantastic that if your fat stores become significantly threatened it will take very effective steps to protect them.


Fat is space efficient, easy to store, doesn't use much energy to sustain, can store an almost unlimited amount of calories; and if your fat cells do get full, your body will simply make new ones to store even more incoming calories.

Controlling your body fat levels may not appear to be the most complicated of sciences.  Ask most people how to lose fat and you'll usually get the simplistic answer: eat less and move more!  To a certain extent at a simplistic level this advice works, at least within a certain range of body fat percentages.  That is, the higher one's body fat levels are the more willing those fat stores are to relinquish their fatty acids for use as energy; whereas when at lower body fat levels, fat tissues become reluctant to part with their fat, becoming resistant or stubborn. 

As complex biological systems we do not strictly operate in compliance with the basic principles of physics.  The human body is not a closed system and the many mechanisms which regulate its vital functions, including body fat regulation, change continually depending upon multiple inter-related factors.

Fundamentally, if you create a calorie deficit where less energy is consumed than your body needs to meet the sum of its basal energy requirements, plus its activity requirements, then you should tap into and burn off your fat stores.

Some nutritional authors claim that the above is a misleading over-simplification of the problem.  To a degree they have a point as poor dietary composition will make fat loss slower and more difficult, and the type of exercise used to accentuate fat loss can have dramatically varying results.

However it has to be said that regardless of which ever route one does take there is no escaping the fact that calorie balance, or more precisely imbalance, is critical!  There is no such thing as an eat all you want fat-loss diet, unless the composition of the diet causes you to want less, and in turn you eat less calories than your body actually burns, either due to physiological effects such as ketone and NEFA suppression of appetite, or because a diet is simply so unpalatable that you choose not to eat much!

It is also misleading of some researchers to suggest that exercise is not a worthwhile tool in the regulation of body fat and as a treatment for obesity.  It is true that good exercise will always struggle to fix the metabolic problems caused by a poor diet, unless the diet is improved.  A balanced and intelligent exercise regime, tailored to individual needs, combined with an intelligent diet will synergistically and powerfully accentuate fat-loss. 

Some of the complications which compound the theories of calorie balance are evident when considering the concept of partitioning. For some introductory information to this read this short post - A Basic Introduction to Calorie Partitioning.

From a body fat management perspective, what we are really interested in, more so than just a calorie deficit, is a fat deficit.  Essentially to lose body fat you need to create a fat deficit. This means that you must be burning more fat than your body is consuming or creating.  To maximise fat loss you need to optimise this process.

Some genetically gifted people, the sort who can eat whatever they like and never gain a pound, are able to easily access and use their body fat more effectively than most normal people, even when eating a standard mixed diet with plenty of carbohydrates. This most likely occurs because they have an excellent natural ability to partition different types of fuel.  They are able to continue burning fats when glucose is freely available but is needed to replenish the body’s glycogen stores, and they efficiently use glucose as a primary fuel without rushing it into fat stores when its supply dominates. They are also likely to have favorable body fat distribution, with less stubborn fat, and probably less fat cells in general.

Unfortunately for them this genetic luck doesn’t always correlate with good health, nor does it tend to last forever.  Usually when they reach their late thirties and beyond, their physiology can become resistant, glucose management starts to falter, and the fat starts to show.  Having a tendency to shunt excess carbohydrates into fat storage via efficient fat tissue de novo lipogenesis may actually help protect individuals from the chronic ravages of high blood glucose levels over the years.

With the right kinds of dietary modification and exercise, you can significantly improve your partitioning ability so that your body will eagerly conserve glucose and proteins, whilst preferentially burning fats for fuel, thus making your regulation of body fat less of an up-hill struggle.

Dietary fat

Let's start with dietary fat, the fat that's found in your food.  All dietary fat is technically packaged as a triglyceride, which is a glycerol molecule bound to three fatty acids.  These fatty acids come in various different sizes and types, with chemical differences which can impact upon physiology, metabolism, and health. They can vary in length from short to long chain, with corresponding numbers of carbon atoms. They also vary in their degree of saturation, which is determined by their number of double bonds.  Saturated fats have no double bonds, monounsaturated fats have a single double bond, and polyunsaturated fats have multiple double bonds. 

When digested and absorbed in the intestines, fats are packaged into lipoproteins called chylomicrons, and transported via the lymphatic system into the bloodstream.  For more detail on this process see my article entitled “Lipoprotein Physiology”.

A number of hours after eating, these chylomicrons will reach the various target tissues; including muscles, the heart, adipose, and the liver. The tissues which need fats to burn as fuel, or to replenish their fat stores, express an enzyme called lipoprotein lipase (LPL) which draws the fatty acids from the chylomicron.

The fate of these fatty acids when they reach these tissues depends upon a number of factors determined by your current metabolic state.  Obviously, to reduce body fat levels we want all incoming fatty acids to be used or burned rather than stored, whilst ideally we also want stored body fat to be tapped into and burned.

Body fat

Body fat, like digested fats, is stored as a triglyceride inside fat cells in various types of fat tissue, as well as within the muscles, called intramuscular triglycerides.

Way back in 1965 Jules Hirsch observed that the fatty acid composition of body fat closely resembles that of the diet.  In trials he found that when subjects were given different controlled fatty acid compositions in their diet for sufficient time to allow for whole adipose turnover, their adipose fatty acid composition changed to closely resemble that of the dietary fatty acid composition. 

An average sized person will have somewhere in the region of 25-30 billion fat cells which are composed of about 90% triglyceride, with the remaining 10% being water and the enzymatic machinery which controls their cellular metabolism.

There are 5 main different types of body fat: essential, brown, visceral, intra-muscular and subcutaneous. 

Essential body fat

Essential body fat; in the brain, nervous system, and other tissues; accounts for about 5% of men’s body mass, and about 10% of women’s body mass.  It’s called essential because without it you wouldn’t be alive.  Women are genetically programmed to retain a higher minimum 'essential' level of adiposity to prepare them for pregnancy and lactation.  These differences underlie one of the main reasons why a women’s body fat percentage cannot, in the vast majority of cases, drop to the single digit levels that men can achieve.

Brown fat

Brown fat is a unique type of fat which actually oxidises the other types of fat to produce heat. In contrast to the other types of fat, which are primarily triglyceride, brown fat consists mainly of mitochondrial mass (the energy production reticulum of the cell), with very little triglyceride. This high mitochondrial density makes brown fat ideal for burning fatty acids for the creation of heat. Animals tend to have significant amounts of brown fat, which they use to generate heat.  

Until recently it was believed that humans did not retain their brown fat beyond infancy, which pretty much discounted it as a factor in adult body fat regulation.  However, from scans carried out to detect metabolic activity in tumours, it has recently become clear that some adults do indeed possess brown adipose tissue, predominantly around the neck and shoulder area, and that the metabolic activity of this tissue increases in response to exposure to cold.

Visceral fat

Visceral fat, also known as organ fat or intra-abdominal fat, is located inside the abdominal cavity, packed in between organs. An excess of visceral fat is known as central obesity as it creates a pregnant look, causing the abdomen to protrude. Excess visceral fat is linked to diabetes, insulin resistance, inflammatory diseases, and other obesity-related diseases.

Men tend to have more visceral fat than women as it tends to correlate with both testosterone and cortisol levels.  

Female sex hormones correlate with increased fat storage in the buttocks, thighs, and hips in women. When women reach menopause and their estrogen levels decline, fat migrates from their buttocks, hips and thighs to their waist.  

When researchers pump sex-change patients up with hormones, they see a shift in bodyfat: men take on female bodyfat patterns and vice versa.  Female athletes and body-builders who use anabolic steroids, or who have higher than normal testosterone levels, also tend to accumulate visceral fat.

When losing body fat, visceral fat is lost relatively easily compared with subcutaneous fat, so by the time men reach the 11-14% body fat range, it is unlikely that they will carry much visceral fat, unless they have been using steroids.

Because dieters are generally more aware and conscious of their subcutaneous fat levels, the preferential use of visceral fat before subcutaneous fat by the body in response to dieting can give the impression that the diet is failing to remove visible fat!  This occurs because visceral fat has a better blood supply, is more insulin-resistant, and has a greater sensitivity to adrenal fat-burning stimulation.  So when losing fat this is generally burned faster and more significantly than subcutaneous fat.  When the visceral fat drops to the lower levels mentioned above the contribution of subcutaneous fat to energy provision increases.  This is also when fat loss becomes much more dependent upon the right hormonal environment.

Intramuscular fat

Intramuscular fat is stored, as its name suggests, within muscles (predominantly next to the more aerobic fibre sub-types) as triglycerides (IMTG).  In a fatty cut of beef IMTG can be seen as the marbling in the meat.  

In humans eating a mixed diet, the excess accumulation of intramuscular fat is associated with insulin resistance and type-2 diabetes among the normal population. However, in fat adapted humans with low carbohydrate intakes, plentiful IMTG storage it is likely to be normal, healthy, and advantageous.

Endurance athletes often do not exhibit the insulin resistance associated with higher levels of IMTG.  They are typically insulin sensitive while having high levels of IMTG, due to their muscles’ trained ability to process both fats and carbohydrates.

Women have been shown to use more IMTG during exercise than men, which directly correlates to the higher IMTG content in women.

IMTG stores act as an energy buffer zone or intermediate energy reservoir, ensuring a consistent rate of supply of fatty acids commensurate with demand for their oxidation, at times when plasma free fatty acid levels may fluctuate in response to varying metabolic conditions.

Subcutaneous fat

This is the kind of fat we all love to hate!  Subcutaneous fat is found just below the skin in a region called the hypodermis. 

As mentioned earlier, due to hormonal differences, in men subcutaneous fat tends to accumulate around the midsection and low-back; whereas in women, it tends to be on the hips and thighs.  This hormonal influence is generally the reason for kids displaying different body fat accumulation patterns before and after puberty.

Not all subcutaneous fat appears to have been created equal!  It appears to exist along a continuum ranging from normal, to what has become termed as stubborn fat.  This can be very difficult for some people to lose.  It comes off last, if it ever comes off at all, and it’s generally stored where you want it the least – around the 6-pack and low back in men, and hips and thighs on women.

To fully appreciate the complexity of body fat one needs to be aware that rather than just being a simple and inert energy store, fat tissue is an element of the endocrine system, secreting powerful self-regulating hormones such as leptin, resistin, and also cytokines. 

To complicate matters further, the various different types of fat tissue behave differently in response to the fat mobilisation signals initiated by the brain and endocrine system.  The fat tissues possess different degrees of blood supply and insulin sensitivity; complicated even further by their specific type and distribution certain adrenoreceptors; which in turn are affected by thyroid hormones and testosterone levels.  The distribution and density of the enzyme lipoprotein lipase (LPL), which determines the rate of fat uptake of a fat cell and the pattern of fat distribution around the body, is also influenced hormonally. 

Fat also behaves differently in relation to a person's total fat mass, that is, the fatter someone is the more willing the fat tissue is to relinquish its stores, and vice versa.

The complexity of body fat regulation is apparent not only in our varied individual tolerance to carbohydrate intake and insulin responses to food, but also in the individual variability of our body fat's responsiveness to hormonal cues for both energy storage and energy liberation.

All these factors impact upon fat's behavior and response to various nutrition and exercise interventions, and highlight some of the potential short-comings of the energy balance paradigm.  In short, it is not advisable to view the human body like an abacus counting calories in versus calories out, whilst this approach works in a strictly controlled lock-down system ( see the Minnesota Starvation Experiment), it is difficult for most normal people to adhere to in normal life.  It is true that for a diet to be successful it needs a calorie deficit, but for sustainability it also needs to be holistic and consider the effects of various foods upon appetite, hunger drivers, psychology, nutrition, long-term health, and so on.

Personally, I have had success with diets at both ends of the spectrum.  As a triathlete training over 20 hours per week, I found a low-fat, high-carb diet effective, but this had to be monitored tightly with calorie recording.  High volumes of full-spectrum aerobic exercise will use a lot of carbohydrates, thus physiologically creating a consistent exercise induced low-carbohydrate state within the body, which in turn results in good use of fat stores during exercise and recovery.  Without lots of exercise the low-fat, high-carb system requires lots of self-discipline and a significant amount of hunger.

At the other end of the spectrum, I have had great success eating a ketogenic diet.  I found this most effective when exercising less, especially at non-competitive intensities.  Dietary induced fat-adaption, combined with intermittent fasting and regular low- to moderate-intensity aerobic exercise helps burn off fat stores very effectively, without feeling hungry all the time.  You will however need to be disciplined in your eating, as carbohydrates will be missed, and calories do still matter.  One also needs to be aware of the insulinogenic capacity of proteins, like beef for example.  For this reason I tend to reserve my protein intake for the evening meal.

Lipoprotein Metabolism & Heart Disease

Lipoproteins are the microscopic vessels used to transport cholesterol, fat, and other fat-soluble nutrients around the body in our circulation.

Studying the metabolism of lipoproteins, their various pathways, regulatory mechanisms, and pathological consequences of chronic disturbances of their metabolism, potentially provides some interesting clues to the ideal composition of the human diet.

For a more detailed explanation and a collection of video tutorials go to Lipoprotein Physiology.

Dyslipidemia

Dyslipidemia is defined as an abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to an unhealthy diet and lifestyle. 

Blood lipid levels range from normal and healthy, through to the extremes of hyperlipidemia, which if untreated can have life-threatening consequences.  

The image on the left is a 4mL sample of hyperlipidemic blood with lipids separated into the top fraction.

For the purposes of this discussion we are most interested in the dyslipidemia which is caused by poor diet and lifestyle, rather than dyslipidemias caused by genetic factors.

As detailed in my articles on Lipoprotein Physiology and Heart Disease, the complications which result in atherogenic dyslipidimea stem from alterations in lipoprotein metabolism and lipoprotein particle morphology.

The sequential domino effect leading to atherogenic dyslipidemia  is as follows:

High levels of hepatic triglyceride formation result in the formation of high numbers of large VLDL particles.  The production of irregular VLDL particles, in quantity and size, is considered to be the most significant contributing factor to unhealthy lipoprotein metabolism (Ref). 

These VLDL particles compete with chylomicrons for interaction with the lipoprotein lipase enzymes at the endothelium of the blood vessels associated with the peripheral tissues.  However, the removal of triglycerides from lipoproteins into peripheral tissues is a saturable process, reflecting the limited activity of lipoprotein lipase, this is known as the common saturable removal mechanism. 

To make matters worse for this overabundance of new large VLDL, the lipoprotein lipase enzyme has a higher affinity for chylomicrons than the VLDL particles, which means that the VLDL particles are forced to wait.  These VLDL particles therefore become susceptible to modification in circulation. 

Through the delipidation cascade, triglyceride rich VLDL become increasingly smaller and undergo further delipidation by hepatic lipase, which has an increased affinity for smaller particles, they then become precursors for the formation of atherogenic small-dense LDL particles (Ref).

These small-dense LDL are deemed more atherogenic as they either penetrate into gaps in the endothelial lining, or because they don’t bind well with the LDL receptor, leading to an excessive time in circulation (Ref , Ref), which in turn increases their susceptibility to oxidation (Ref). 

If an individual’s diet is high in omega-6 fatty acids these particles become even more prone to oxidation, thus increasing their atherogenic potential even further (Ref).

Elevated triglyceride levels also negatively impact upon HDL metabolism.  In response to elevated triglyceride levels, the actions of cholesterol ester transfer protein (CETP) causes apolipoproteins and lipids to exchange between triglyceride-rich lipoproteins and HDL particles (Ref).  This leads to triglyceride-rich HDL being more susceptible to modification by hepatic lipase (Ref), which as I detailed in here, leads to the formation of smaller HDL particles which leave circulation sooner, thus detracting from the overall positive contribution of HDL metabolism. 

The above inverse relationship between plasma triglycerides and HDL has been observed in many studies.

Putting all of the above into a nutshell:

Excessive levels of endogenous triglyceride production (High VLDL produced by the liver), results in a cascade of negative lipoprotein interactions, forming a high number of abnormal particles which are vulnerable to oxidative damage (which is exacerbated when high dietary levels of PUFA are thrown into the mix). 

When these damaged and oxidised particles are incorporated into the arterial lining, either due to a lipoprotein abnormality or simply as part of the normal process of cholesterol provision for repair of the endothelium, they trigger a spiral of inflammation and immune reactions which result in the formation of arterial plaques.

Allow the above process to occur repeatedly over a number of decades and you may unfortunately be increasing your chances of being one of the unlucky majority who dies prematurely from a heart attack!

Defining High Triglycerides

Adult Men                    Lower level = Your age                       High= 200mg/dl (2.3mmol/L)

Adult Women              Lower level = Your age                       High = 165mg/dl (1.9mmol/L)

Addressing the dietary cause of high triglycerides

In the well-fed state, when there is an excessive supply of calories, especially from carbohydrates, if the liver cannot store or oxidise incoming calories due to shear rate of delivery, or quantity in relation to available storage space, it will up-regulate hepatic glucose output (regardless of increasing plasma insulin levels) pushing the excess glucose into the blood for peripheral tissues to deal with.  Simultaneously, it will initiate de novo lipogenesis (DNL) – the creation of new fat – which is then packaged into large numbers of VLDL particles for export.

This hepatic DNL has been found to only amount to about 5-10grams per day in response to carbohydrate over-feeding.  This is not a significant amount of fat when viewed purely from a body fat regulation perspective, however, from a health perspective 5-10 grams corresponds to a huge number of VLDL particles.

Increases in fasting plasma triglyceride concentrations are commonly observed during the consumption of diets with higher energy contributions from carbohydrates. 

This study  reported that a low-fat (15%), high-carbohydrate diet resulted in a 60% elevation in triglyceride production, and a 37% reduction in VLDL triglyceride clearance, when compared with a mixed diet (35% fat) of equal calories.

There is of course an even better way of elevating triglyceride levels – calorie excess from high carbohydrates, especially fructose rich carbohydrates which preferentially saturate liver glycogen stores, combined with an equally high intake of calories from dietary fats, which together will very capably clog up the common saturable removal mechanism!  But that’s just stating the obvious!

In the opposite corner, many clinical trials have demonstrated that carbohydrate restricted diets consistently improve triglyceride levels (Ref1, Ref2).

The bottom line – for a healthy heart, chronically normalise triglyceride levels and omega-6 balance by eating a calorie balanced diet, avoiding excessive carbohydrates and polyunsaturated oils.

Low-PUFA, Low-Carb Nutrition - Harmonious Lipoprotein Metabolism

When writing my article introducing lipoprotein physiology I scratched together the following hypothetical model of ‘harmonious lipoprotein physiology’ based around what I’d expect from a high-saturated fat diet, with low omega-6 PUFA, and a very low-carbohydrate intake.

Harmonious Lipoprotein Metabolism via a High-Saturated Fat, Very Low Carbohydrate Diet?

After complete adaptation to a diet high in saturated animal fats (75% calories), very low in carbohydrates (<25g/day), and centred around a hub of animal based proteins (20% calories) the following pattern of lipoprotein metabolism may predominate.

Exogenously derived triglycerides provide the majority of the body’s total triglyceride supply.  These are delivered directly to the peripheral tissues from the digested saturated fats via chylomicrons. 

Triglyceride contents are rapidly removed by highly active lipoprotein lipase (LPL) in well-conditioned and fat-adapted tissues, with high capacities of fat-oxidation and intramuscular fat storage. 

Chylomicron remnants are efficiently returned to and absorbed by the liver, and quickly recycled providing the dietary-derived cholesterol and some of the lipoprotein components for LDL formation and forward cholesterol transportation to peripheral tissues.

VLDL production is low due to the endogenously balanced and finely regulated flow of plasma free fatty acids, amino acids, ketones and gluconeogenically derived glucose.   LDL formation is therefore balanced and commensurate with peripheral demand for new cholesterol.  ApoB₁₀₀ lipoprotein particle numbers are stable and consistent.  Pattern-A large buoyant LDL particles with generous anti-oxidant profiles predominate in circulation. 

There is limited competition for binding with lipoprotein lipase at peripheral tissue  due to low VLDL production and therefore triglyceride clearance rates are rapid.  The significant reduction in VLDL appearance and their subsequent rapid clearance from circulation, leads to low lipoprotein particle delipidation and therefore negligible production of the atherogenic small dense LDL. 

ApoB particles' triglyceride content should be low in polyunsaturated fatty acids due to the majority of dietary fats being fully saturated, with only essential amounts of polyunsaturated fatty acids for incorporation into peripheral cell membranes, thus reducing the potential for oxidised LDL formation. 

Basal fasting blood glucose levels are low and post-prandial levels will not reach levels capable of causing glycation and the formation of AGEs within particles or to endothelial surfaces.

HDL particle numbers are elevated by the plentiful influx of dietary saturated fats, with low rates of catabolism, creating a high plasma HDL/apoB ratio.  HDLs should therefore have no difficulty meeting the demand for their role as ‘apoprotein lending libraries’. 

Excellent triglyceride clearance will negate the incapacitation of HDL by triglyceride saturation.  Overall, HDL is able to carry out its very important anti-inflammatory, antioxidant and anti-thrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, without any obvious resistance.

End result - plaque free pipes?

_______________________________________________________

After writing the above hypothetical scenario I found this beauty - “Modification of Lipoproteins by Very Low-Carbohydrate Diets” by J.S. Volek et al (2005).

The paper makes a similar, albeit far more precise, proposal of anticipated lipoprotein metabolism in response to a very low carbohydrate diet.

Volek et al propose the following model to explain the modifications in lipoprotein metabolism on a very low carbohydrate diet (VLCD):-

Proposed model of lipoprotein metabolism with consumption of a VLCD that explains the observed decrease in TAG, increase in HDL-C, and redistribution of LDL to a larger particle size. Paths upregulated during consumption of a VLCD are represented by solid lines and those downregulated by dashed lines.

Volek et al - “Repeated ingestion of a VLCD initially increases circulating TAG-rich chylomicrons, which are cleared rapidly by lipoprotein lipase (LPL) bound to the luminal surface of capillary endothelial cells in skeletal muscle and adipose tissue.

Although speculative, we suggest that a VLCD increases muscle LPL, enhancing TAG clearance. A VLCD leads to lower glucose and insulin levels, which decrease LPL and increase hormone-sensitive lipase (HSL), promoting TAG hydrolysis and increasing fatty acid (FA) rate of appearance.

LPL-mediated lipolysis of chylomicrons results in release of FA that is either taken up by the underlying tissue or escapes into the circulation. Any increase in FA delivery to skeletal muscle is balanced by an increase in fat oxidation as evident from the post-absorptive respiratory exchange ratios near 0.7.

Circulating FAs are taken up by the liver and preferentially diverted away from esterification to TAG and toward mitochondrial oxidation to acetyl CoA. Accumulation of acetyl CoA exceeding the capacity for mitochondrial oxidation results in the formation of ketones.

Reduced hepatic production of TAG results in less VLDL synthesis and secretion into the circulation.

LPL-mediated lipolysis of VLDL results in transfer of unesterified cholesterol, phospholipid (PL), apolipoprotein (apo)E,  apoC-II, and apoC-III to form mature HDL-C. The remaining remnant particles are either taken up by the liver or converted to LDL.

Decreased circulating VLDL, particularly in the postprandial period, results in less cholesterol ester transfer protein (CETP)-mediated neutral lipid exchange with LDL-C. A reduction in hepatic lipase (HL) prevents larger LDL-C from being delipidated to smaller, dense (atherogenic) LDL, resulting in a predominance of larger LDL particles.”

HDL & Heart Disease

High Density Lipoprotein & Heart Disease 

It is very well documented that high concentrations of the so-called "good cholesterol" - high density lipoprotein (HDL) - has protective value against cardiovascular diseases such as ischemic stroke and myocardial infarction. Low concentrations of HDL correlate with an increased risk for atherosclerotic diseases.

Similar to some of the other bio markers of cardiac risk, without wanting to willingly state the obvious, it is important to recognise that low-HDL levels are merely one of the symptoms of the cause of heart disease.

Guidelines suggest that men are at risk with HDL levels of 40 mg/dL (1.0 mmol/L) or less, whereas levels of 60 mg/dL (1.6 mmol/L) or above are described as desirable.  Women are considered to be at risk if HDL levels are 50 mg/dL (1.3 mmol/L) or less, while levels of 60 mg/dL (1.6 mmol/L) or above are described as desirable.

HDL is the smallest of the lipoprotein particles, it is also the densest lipoprotein as it contains the highest proportion of protein.

HDL carries many different types of lipid and proteins, several of which have very low concentrations but are biologically very active.  For example, HDL and their protein and lipid constituents have very important anti-inflammatory, antioxidant and anti-thrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk.

Men tend to have noticeably lower HDL levels, with smaller size and lower cholesterol content than women. This is coincidental with an increased incidence of atherosclerotic heart disease in men.

The importance of normal to high levels of HDL is reflected in the observation that people with very low LDL levels remain exposed to increased cardiac risk if their HDL levels are not high enough.

Anecdotally, I have encountered reports of individuals increasing HDL values from normal levels to over 80mg/dl, whilst decreasing triglycerides from over 150 down to 50mg/dl when adopting a very-low-carb, high saturated-fat diet.

HDL as an indirect forward transporter

The metabolism of HDL is very complex, and there are many different types of HDL. 

In a nutshell, HDL is an apoA lipoprotein which is made either by the small intestine or the liver, and in contrast to the apoB lipoproteins (Chylomicrons, VLDL, IDL, LDL) which primarily forward transport cholesterol and lipids to peripheral tissues, HDL is considered mainly as a reverse transporter of cholesterol from peripheral tissue to the liver, or to steroid producing organs such as the adrenals, ovary, and testes.

It is important not to view HDL purely as a reverse transporter.  It also plays an important role in enabling the other lipoproteins to deliver their cargos quickly and effectively.  It achieves this by sharing out key protein identification molecules to other lipoproteins in circulation; in effect HDL also functions as a lending library of identification proteins.

For example, HDL donates proteins (apoE and apoC₂) to chylomicrons which are only equipped with apoB₄₈ when they are made in the intestines. These donated proteins are essential for the chylomicrons to deliver their lipid and cholesterol cargo to peripheral tissues. 

Once the chylomicron has delivered 80% of its triglyceride contents it discards its apoC₂ protein and becomes a chylomicron remnant.  This chylomicron remnant now needs to be recycled by the liver. The chylomicron still has its apoE molecule which it got from HDL earlier, which it needs to bind with the LDL receptors at the liver, where it is absorbed and recycled. 

When VLDL is released from the liver it is equipped with the apoB₁₀₀ protein, it then picks up apoE and apoC₂ in circulation from HDL, enabling VLDL to dock at peripheral tissues and release its cargo (apoC₂ is used to dock at peripheral tissues, apoE is used to dock at the liver when it returns as a VLDL remnant). When delivering to peripheral tissues, after 50% of its triglyceride contents are deposited, VLDL discards its apoC₂ protein, becoming a VLDL remnant. 

About 50% of the VLDL remnant particles then return to the liver to be absorbed and recycled, the remainder are transformed into new LDL particles.  This occurs via the interaction of the VLDL remnant and an enzyme called hepatic lipase, which virtually empties the VLDL remnant of its triglyceride contents into the liver.  In the process the apoE identification protein is lost and returned to HDL in the circulation, creating a new LDL particle consisting of an apoB₁₀₀ protein and next to zero triglycerides.

If you have high levels of apoB lipoproteins and low levels of apoA lipoproteins, in other words high triglycerides and low HDL (Triglyceride levels and HDL levels tend to be inversely proportional), the rate of HDL’s protein lending capacity is going to be inferior to the high demand from the large number of apoB lipoproteins needing those apoE and apoC₂ proteins in order to make their deliveries.  This all contributes to increased duration of lipoprotein exposure to unfavorable modification in circulation. 

High HDL is therefore necessary for optimal forward delivery of triglycerides, which may partly explain the increased expression of HDL in response to high-fat nutrition.  This increased HDL expression may be a parallel to increased chylomicron production in the intestines in response to increased dietary fat absorption.

Hopefully, from the above description, it can be appreciated how important high HDL levels are not only as reverse cholesterol transport from tissues, but also as an essential indirect element in the forward process of triglyceride and cholesterol delivery to peripheral tissues via their protein lending capacity.

HDL’s other positive roles.

HDL’s key identification protein is apoA.  The apoA identification protein is important as it allows HDL to dock at peripheral tissue cells which need to off-load cholesterol. 

From an anti-atherogenic perspective, apoA is also very important because it enables HDL to dock at scavenger receptor sites on macrophages which have been consuming oxidised and damaged lipoproteins, facilitating the removal of their waste for return to the liver for healthy excretion, rather than being left to contribute to plaque formation. 

HDL also has an important anti-oxidant role and is responsible for delivering vitamin E to cells.   As demonstrated here, it is 3-5 times more effective than LDL at delivering vitamin E to endothelial cells. LDL appears to deliver vitamin E to these cells simply by being taken up as a whole particle, whereas HDL interacts with what could be called the "HDL receptor" and delivers vitamin E to the endothelial cell at a much faster rate than it would if it were completely consumed by the cell.

When HDL breaks down

Similar to the other lipoproteins, HDL particles can become modified by over exposure to an undesirable environment.  When serum triglyceride levels are continually elevated due to excessive carbohydrate consumption, HDL particles become enriched with triglycerides, making them better targets for hepatic lipase.  As hepatic lipase acts upon the over-fat HDL they become more and more unstable, eventually resulting in the release of their apoA identification protein, rendering them unable to carry out their vital roles.

Dietary influences upon HDL

Diets high in saturated fats and cholesterol have been shown to increase HDL levels both by increasing the transport rates and decreasing catabolic rates of HDL.  It is suggested in this study that this is perhaps as an adaptation to the metabolic load of a high fat diet.

Low-fat diets have repeatedly been found to have the opposite effect by actually decreasing healthy levels of HDL.

As with LDL particles, we also need to look at lipoprotein sub-types when looking at HDL.  Studies have found that the largest and most buoyant HDL particles (HDL2) correlate significantly with HDL's most protective effects. That is, the more HDL2 particles you have, the less your chances of having a heart attack.  Increased levels of the denser HDL3, is reportedly unrelated to reduced coronary disease.

A diet low in fat, compared to one high in total fat and saturated fat, has been demonstrated to significantly reduce levels of these large HDL lipoproteins.  This is not a short-term effect, with studies showing persistent results after 12 months.

This study found that “A reduction in dietary total and saturated fat decreased both large (HDL2 and HDL2b) and small, dense HDL sub-populations, although decreases in HDL2 and HDL2b were most pronounced.” - Berglund et al (1999).  It has also been shown that saturated and omega-3 fats selectively increase desirable large HDL.

Allow naturally healthy HDL levels to florish

In the vast majority of cases, good health is largely about you and what environment you force your body to exist in.  High and healthy HDL levels are a prime example of this.

I was going to discuss how you can elevate HDL levels, but it would be more accurate to say that the following suggestions will allow HDL levels to elevate to their natural levels.

With a healthy diet and lifestyle it is not unrealistic for your HDL levels to exceed 60+ mg/dl.

1)   Firstly and most importantly, gravitate as close as possible towards the very-low-carb, high-fat nutritional model:

• In a study of the effects of “6-month adherence to a very low carbohydrate (<25g/day) diet program”, triglyceride levels decreased 56 ± 45 mg/dL , and HDL cholesterol levels increased 10 ± 8 mg/dL.
• This low-carbohydrate, ketogenic diet study over 6 months observed many beneficial changes in serum lipid subclasses, including a 5% increase HDL particle size, and a 21% increase in large HDL.

2)   Avoid low-fat, high-carbohydrate diets:

• In controlled trials, low-fat, high-carbohydrate diets decrease HDL concentrations. The effect is strongest when carbohydrates replace saturated fatty acids, but is also seen when carbohydrates replace mono- and polyunsaturated fatty acids.  The effect is seen in both short- and long-term trials and therefore appears to be permanent. This finding is supported by epidemiological studies in which populations eating low-fat, high- carbohydrate diets were shown to have low HDL concentrations.
• It has been demonstrated that a low cholesterol, but high polyunsaturated fat diet reduced HDL by 17.4%, highlighting the importance of saturated fat in this respect; and a low cholesterol, very low-fat diet has more dramatic effects upon HDL reducing its levels by 28%.

3)   Perform regular aerobic exercise:

• Perform aerobic exercise regularly at moderate intensity (Sustained walking or light jogging is sufficient)(Ref, Ref). 
• Minimal weekly exercise volume for a modest increase in HDL levels has been estimated to be 900 kcal of energy expenditure per week or 120 minutes of low-intensity exercise per week. 
• In a study comparing runners with sedentary men, the mean HDL cholesterol level was 65 mg mg/dL in the runners and 41 mg /dL in the controls. The lipid-rich HDL2 species accounted for a much higher proportion of the HDL in runners (49% v 29%). Part of the positive adaptation here appears to be related to increased mean biologic half-life of HDL proteins, which was 6.2 days in the runners compared with 3.8 days in the sedentary men.
• In a study of “Miles Run per Week and High-Density Lipoprotein Cholesterol Levels in Healthy, Middle-aged Men” results indicate a dose-response relationship between miles run per week and increased levels of HDL. Most changes were noted in those who ran 7 to 14 miles per week at mild to moderate intensities. The HDL increase was valued at 0.3mg/dl per mile.
• In many studies changes in HDL levels are not large and it is suggested that the potential for exercise-related changes in HDL may be modest in many subjects.  However, in studies where insignificant to low exercise induced rises in total HDL are reported, results can be misleading without an accurate assessment of the HDL subfractions.  Heart healthy HDL2 can rise in line with proportional decreases in HDL3, resulting in an insignificant change in total HDL, but with an underlying very desirable upswing in HDL2 levels (Sample).

4)   Consider supplementing your diet with omega-3 fish oil:-

(Note: Due to its highly unstable nature I wouldn’t touch flax seed oil with a barge-pole! Also, the following benefits appear to be exclusive to marine derived n-3 PUFA.  If following a genuinely low-carbohydrate diet with plenty of pasture raised animal food sources supplementation is likely to be unnecessary.)

• After 8 weeks a 40% increase in HDL2 cholesterol was reported in response to supplementation of 1.88 g of eicosapentaenoic acid [EPA] and 1.48 g of docosahexaenoic acid [DHA] per day. 
• This study of 6 weeks supplementation of 2.8g/d of eicosapentaenoic acid (EPA) and 1.7g/d of docosahexaenoic acid (DHA) the levels of total HDL-cholesterol did not change, however  HDL2 increased by a whopping 74%, with a concomitant 19% decrease of HDL3.

If not following low-carb, high-sat-fat nutrition you could consider a niacin supplement (Vitamin B3):-

• Niacin has a well-documented history in the treatment of heart disease.  For an easily available and modest vitamin it has relatively powerful lipoprotein regulating ability, including a down-regulation of triglyceride, VLDL, and LDL production; whilst increasing HDL levels.
• This trial used between 1,000 and 2,000 mg/day over 12 weeks, and reported dose-proportional benefits using an extended release formula.  It is worth noting that continuous daily 24 hour exposure to niacin over an extended period can be toxic to the liver, therefore self-prescription of very-slow-release niacin should be avoided.
• However, taking niacin may be considered to be a mere biochemical shortcut.  Niacin acts through the beta-hydroxybutyrate (ketone body) receptor.  In effect by taking these large doses of niacin you are simply mimicking ketones and fooling the body into thinking that its primary fuel source is fats, creating the positive metabolic processes which ketogenic nutrition triggers – down-regulation of VLDL, decrease in TAG, increase in HDL-C, and redistribution of LDL to a larger particle size.

NOTE:   If you are eating a high-saturated fat intake with very low carbs you will have all the positive lipoprotein benefits nature intended, without touching a niacin supplement.

NOTE2:  Moderate to low alcohol consumption has inconclusive effects upon HDL levels:

• Whilst alcohol consumption correlates with both reduced coronary heart disease and increased plasma HDL cholesterol concentrations, the HDL mediated cardio-protective effects of moderate alcohol consumption appear inconclusive.  Previously reported rises in total HDL appear to be more associated with increases in the inert HDL3 with insignificant changes in the cardio-protective HDL2. [Ref1 , Ref2].
• The beneficial effects associated with the consumption of red wine with meals, appears to be more related to its capacity to reduce the susceptibility of human plasma and LDL to lipid peroxidation, rather than via possible influences upon HDL.)